rs28897672

chr17-43106487-A-Cchr17-43106487-A-Gchr17-43106487-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):c.181T>G(p.Cys61Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000187 in 1,604,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C61F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:59 O:3
• Conservation: PhyloP100: 5.10

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_007294.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43106487-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 54360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-43106487-A-C is Pathogenic according to our data. Variant chr17-43106487-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 17661.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43106487-A-C is described in Lovd as [Likely_pathogenic]. Variant chr17-43106487-A-C is described in Lovd as [Pathogenic]. Variant chr17-43106487-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.181T>G	p.Cys61Gly	missense_variant	4/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.181T>G	p.Cys61Gly	missense_variant	4/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250754 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135582

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1452604 Hom.: 0 Cov.: 28 AF XY: 0.0000194 AC XY: 14 AN XY: 723022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000208

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:59 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:22 Other:2

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 18, 2013	- -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 13, 2022	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PS3, PS4_STR, PM5_STR, PP1 -
Pathogenic, criteria provided, single submitter	research	Institute of Genomics, University of Tartu	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 05, 2021	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.181T>G, in exon 4 that results in an amino acid change, p.Cys61Gly. This sequence change has been described in the gnomAD database with a low population frequency of 0.0032% (dbSNP rs28897672). The p.Cys61Gly change affects a highly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Cys61Gly substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in a significant number of individuals with breast and ovarian cancer (PMID: 7894493, 10788334, 21324516, 20180014, 20345474, 20507347, 20569256, 19594371). Experimental studies have also demonstrated that this variant disrupts several aspects of BRCA1 function (PMID: 11278247, 9525870, 22172724, 23161852, 23867111). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Cys61Gly variant has been identified in 64 out of 16070 proband chromosomes (frequency 0.004) in individuals with unilateral and contralateral breast cancers, ovarian cancers and familial breast and ovarian cancer phenotype, and also found in 4 out of 12088 control chromosomes (frequency <0.0001) included in these studies (Bergthorsson 2001, Brozek 2011, Bogdanova 2010, Capanu 2011, Elsakov 2010, Friedman 1994, Scott 2003, Uglanitsa 2010, Zhang 2011). It is listed in dbSNP database presented “with probable pathogenic allele” (ID#: rs28897672) however no frequency information was available. The p.Cys61 residue is highly conserved in mammals and other species; however, computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. Functional studies have shown that this variant abolishes ubiquitin ligase activity of the BRCA1-BARD1 heterodimer and impairs BRCA1 DNA repair function, and therefore, it was considered as a pathogenic mutation (Au 2005, Brzovic 2003, Houvras 2000, Millot 2011, Morris 2004, Morris 2006, Ransburgh 2010, Ruffner 2001, Sweet 2010, Caliqo 2009, Humphrey 1997). In addition, this variant has been presented as a clinically important variant in the UMD (40 times) and the BIC (230 times) databases. In summary, based on the above information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 12, 2015	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 04, 2023	Criteria applied: PS3,PS4,PP3,PS1_mod, PP4_PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Pathogenic, no assertion criteria provided	research	Medical Genetics, Medical University Pleven	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	The c.181T>G (p.Cys61Gly) variant has been detected in a multiple patients with breast and ovarian cancer [PMID 20507347, 21965345, 21503673, 20180014, 20345474, 23695190, 24728189, 21324516, 20569256 among others] and prostate cancer [PMID 27433846]. Functional in vitro assays showed that this variant was deleterious [PMID 23867111]. This variant has been reported in 8 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/17-41258504-A-C). This variant occurs at high frequency in Eastern European countries and is considered a founder mutation in these countries [PMID 20507347, 20345474]. Cysteine at amino acid position 61 of the BRCA1 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms predict this p.Cys61Gly change to be deleterious. Other changes affecting the same amino acid have been reported in patients with breast and/or ovarian cancer (p.Cys61Arg, p.Cys61Ser, p.Cys61Tyr). This variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 06, 2024	The c.181T>G (p.Cys61Gly) variant of BRCA1 has been detected in multiple individuals with breast and ovarian cancer (PMID: 7894493, 10447273, 10788334, 11102977, 19594371, 20180014, 20345474, 20507347, 20569256, 20180014, 21324516, 21503673, 21965345, 23695190, 24728189, 29492181) and prostate cancer (PMID: 27433846). Functional in vitro assays showed that this variant increases proteolytic susceptibility of the COOH-terminal portion of the NH2-terminal domain and perturbs the oligomerization properties of BRCA1 (PMID: 9525870), fails to reverse radiation hypersensitivity (PMID: 11320250), and damages ubiquitin ligase activity (PMID: 11278247). This variant has been reported in 7 non-Finnish Europeans from gnomAD. This variant occurs at high frequency in Eastern European countries and is considered a founder mutation in these countries (PMID: 20507347, 20345474). Cysteine at amino acid position 61 of the BRCA1 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms predict this p.Cys61Gly change to be deleterious. Other changes affecting the same amino acid have been reported in individuals with breast and/or ovarian cancer (p.Cys61Arg, p.Cys61Ser, p.Cys61Tyr). This variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2000	- -

not provided Pathogenic:16

Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 30, 2020	The BRCA1 c.181T>G; p.Cys61Gly variant (rs28897672) has been reported in individuals with breast or ovarian cancers (Friedman 1994, Zhang 2011). Additionally, other variants at this codon (p.Cys61Arg, p.Cys61Tyr) have been reported in families with breast and ovarian cancer and are considered pathogenic (Abkevich 2004, Al-Mulla 2009). The p.Cys61Gly variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 17661), and it is found in the general population with an overall allele frequency of 0.003% (8/250,754 alleles) in the Genome Aggregation Database. The cysteine at residue 61 is highly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, BRCA1 protein containing the p.Cys61Gly variant fails to homodimerize (Brzovic 1998), fails to protect the cell from radiation hypersensitivity (Ruffner 2001), and does not mediate homologous recombination repair upon DNA damage (Ransburgh 2010). Based on available information, the p.Cys61Gly variant is classified as pathogenic. References: Abkevich V et al. Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet. 2004; 41(7):492-507. Al-Mulla F et al. Age-dependent penetrance of different germline mutations in the BRCA1 gene. J Clin Pathol. 2009;62(4):350-6. Brzovic P et al. The cancer-predisposing mutation C61G disrupts homodimer formation in the NH2-terminal BRCA1 RING finger domain. J Biol Chem. 1998; 273(14):7795-9. Friedman L et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet. 1994; 8(4):399-404. Ransburgh D et al. Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination. Cancer Res. 2010; 70(3):988-95. Ruffner H et al. Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci U S A. 2001; 98(9):5134-9. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011; 121(2):353-7. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2020	Recurrent founder variant in the Polish, German, Czech Republic, and Austrian populations (Karami 2013); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Published functional studies demonstrate a damaging effect: variant shown in both mouse and in vitro studies to disrupt proper function of the BRCA1 protein (Ruffner 2001, Chang 2009, Ransburgh 2010, Drost 2011); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 300T>G; This variant is associated with the following publications: (PMID: 10788334, 22843421, 22172724, 21503673, 24489791, 21965345, 20345474, 22006311, 21324516, 20507347, 15235020, 7894493, 24516540, 27928164, 18097605, 9663595, 29339979, 29433453, 28477318, 29335924, 11320250, 19770520, 20103620, 21990134, 24312913, 17319787, 16168118, 9525870, 18680205, 20180014, 21922593, 23867111, 24728189, 23695190, 24504028, 21520273, 19543972, 25782689, 27043660, 26852130, 26779294, 24528374, 27194814, 26915939, 28123851, 26246475, 26689913, 27153395, 27433846, 25085752, 27836010, 25823446, 26681312, 27272900, 20569256, 28166811, 11802209, 19594371, 28454591, 28503720, 28495237, 28324225, 28285342, 18489799, 29492181, 23161852, 30209399, 30219179, 27978560, 28423363, 29310832, 30067863, 29506128, 29446198, 30720243, 30322717, 31090900, 31159747, 30918533, 31347298, 31209999, 30079159, 30040829, 29254167, 26656232, 26183948, 25814778, 23788959, 23397983, 21232165, 20683152, 20567915, 33484353, 25525159, 31447099, 32341426, 32719484, 14986830, 32885271, 33087888, 33507482, 33674644) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 13, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 03, 2023	The frequency of this variant in the general population, 0.000062 (7/113480 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMIDs: 35464868 (2022), 33507482 (2021), 33484353 (2021), 32885271 (2021), 32854451 (2020), 32719484 (2020), 32341426 (2020), 31347298 (2019), 31090900 (2019), 29492181 (2018)). Functional studies report the variant is damaging to proper BRCA1 function (PMIDs: 33087888 (2021), 30209399 (2018), 27272900 (2016), 25823446 (2015), 23867111 (2013), 20103620 (2010), 15569676 (2005), 11320250 (2001). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BRCA1: PM1, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, PP1 -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 61 of the BRCA1 protein (p.Cys61Gly). This variant is present in population databases (rs28897672, gnomAD 0.006%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7894493, 10788334, 20180014, 21324516). It is commonly reported in individuals of Eastern European ancestry (PMID: 19594371, 20345474, 20507347, 20569256). This variant is also known as 300T>G. ClinVar contains an entry for this variant (Variation ID: 17661). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 9525870, 11278247, 22172724, 22843421, 23161852, 23867111). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2017	Variant summary: The BRCA1 c.181T>G (p.Cys61Gly) variant involves the alteration of a conserved nucleotide that leads to the alteration of an amino acid residue in the RING domain of BRCA1 protein (InterPro). 4/5 in silico tools predict a damaging outcome for this variant and several functional studies demonstrated the Cys61Gly mutation affects several functional properties of the BRCA1 NH2-terminal domain (e.g. Brzovic 1998, 2003). This variant was found in 8/119006 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000122 (8/65364). This frequency is smaller than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This is a well established disease variant that was reported in multiple patients with HBOC (e.g. Friedman 1994, Gorski 2000, Thorstenson 2003, Bogdanova 2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 08-22-2015 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2019	The p.Cys61Gly variant in BRCA1 has been identified in >300 individuals with BRCA1-associated cancers and has segregated with disease in multiple families, including one male with breast cancer (Friedman 1994, Gorski 1999, Cherbal 2010, Bogdanova 2010, Breast Cancer Information Core database, www.research.nhgri.nih.gov/bic/). This variant has been identified in 8/65364 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs28897672). Please note this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. In vitro functional studies have shown that the p.Cys61Gly variant disrupts protein function and produces drug-resistant tumors in mouse models (Brzvoic 1998 and Drost 2011). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon segregation studies, presence in affected individuals, low frequency in controls, and functional evidence. The ACMG/AMP criteria applied: PS4, PS3_M, PP1_M, PM2_P. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	-	- -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 05, 2023	The c.181T>G (p.C61G) alteration is located in coding exon 3 of the BRCA1 gene. This alteration results from a T to G substitution at nucleotide position 181, causing the cysteine (C) at amino acid position 61 to be replaced by a glycine (G). Based on data from gnomAD, the G allele has an overall frequency of 0.003% (8/250754) total alleles studied. The highest observed frequency was 0.006% (7/113480) of European (non-Finnish) alleles. The p.C61G mutation impacts a critical residue in the RING finger functional domain of BRCA1, represents a common mutation in European populations, and has been identified in patients with breast, ovarian, pancreatic, and prostate cancer (Gronwald,2006; Janaviius, 2010; Meisel, 2017; Brand,2018; Ibrahim, 2018). This alteration has been classified as definitely pathogenic (p>0.99) by a multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton, 2007; Lindor, 2012; Vallee, 2012). Of note, this alteration is also designated as 300T>G in older published literature. This amino acid position is highly conserved in available vertebrate species. This alteration has been shown to cause defective homology-directed recombination DNA repair as well as defective single-strand annealing repair (Towler, 2013). In addition, one functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	This missense variant replaces a conserved cysteine with glycine at codon 61 in the RING domain of the BRCA1 protein. Functional studies have shown that this variant disrupts the oligomerization properties of BRCA1 (PMID: 9525870), abolishes interaction with BARD1 and ubiquitin-ligase activity associated with BRCA1 (PMID: 11278247, 11320250), inhibits BARD1-dependent repression of BRCA1 transcriptional activity (PMID: 18243530), abolishes homology-directed DNA repair activity (PMID: 20103620), and renders the mutant protein unable to complement BRCA1-null mouse or human haploid cells (PMID: 23867111, 30209399). This variant is a common cause of breast and ovarian cancer in individuals of Eastern European ancestry (PMID: 10447273, 10788334, 11102977, 20345474, 20507347, 20569256, 29492181) and has been shown to be a founder mutation in the Polish population by haplotype analysis (PMID: 19594371). This variant has been identified in 8/250754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -

Familial cancer of breast Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change replaces cysteine with glycine at codon 61 of the BRCA1 protein (p.Cys61Gly). The cysteine residue is highly conserved among species and is located in RING finger domain of the BRCA1 protein. There is a large physiochemical difference between cysteine and glycine (Grantham Score 159). This variant is present in population databases (rs28897672, 0.01%) and has been reported in the literature as a common cause of breast and ovarian cancer in individuals of Eastern European ancestry (PMID: 20345474 ; 19594371). It has been reported in hundreds of individuals affected with these cancers (PMID: 21324516 ). It is also known as 300T>G in the literature. The mutation database ClinVar contains entries for this variant (Variation ID:17661 )Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging. In addition, experimental studies have shown that this variant disrupts several aspects of BRCA1 function (PMID: 22172724, 23867111 ). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 29, 2022	_x000D_ Criteria applied: PS3, PS4, PM5, PM2_SUP, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostics Centre, Carl Von Ossietzky University Oldenburg	Oct 16, 2023	The variant BRCA1:c.181T>G, p.(Cys61Gly) which is located in the coding exon 4 of the BRCA1 gene, results from a thymine to guanine substitution at nucleotide position 181. The cysteine at protein position 61 is replaced by glycine, an amino acid with significantly different properties. Co-localised variants have been described as pathogenic (p.(Cys61Tyr), ClinvarID:54364; p.(Cys61Arg), ClinvarID:54360). This position is directly involved in the binding of a Zn2+ ion and is located in the RING finger domain of the BRCA1 protein. In silico tools predict a severe deleterious effect for the variant (REVEL = 0.95). The variant is as very rare with an overall population allele frequency= 0.00003285 (gnomAD V3.1.2). In Clinvar, this mutation has been consistently classified as pathogenic in 59 entries (ClinvarID: 17661). Numerous publications have associated this alteration with an increased risk of breast cancer (PMIDs:7894493, 10788334, 20683152, 20569256). Functional studies have shown a disruptive effect of this alteration on the function of BRCA1 and a resistance to therapy of tumours with this alteration (PMIDs: 22172724, 9525870, 11278247, 18243530). The variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -

Breast carcinoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 24, 2022	_x000D_ Criteria applied: PS3, PS4, PM5_STR, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 06, 2016	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

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Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

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Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2022

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Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;.;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N;N;N;D;N;D;D;D;N;.;N;D;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G	Uncertain	0.011	D;D;D;T;D;T;.;T;D;.;D;D;.;.
Polyphen		0.12, 1.0	.;B;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.98
MutPred		0.99		Gain of disorder (P = 0.0488);Gain of disorder (P = 0.0488);Gain of disorder (P = 0.0488);Gain of disorder (P = 0.0488);.;Gain of disorder (P = 0.0488);Gain of disorder (P = 0.0488);.;Gain of disorder (P = 0.0488);Gain of disorder (P = 0.0488);Gain of disorder (P = 0.0488);Gain of disorder (P = 0.0488);Gain of disorder (P = 0.0488);.;
MVP		1.0
MPC		0.45
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28897672; hg19: chr17-41258504; COSMIC: COSV105897801; COSMIC: COSV105897801;