rs80357446

Positions:

• chr17-43115729-C-A
• chr17-43115729-C-G
• chr17-43115729-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000357654.9(BRCA1):​c.131G>T​(p.Cys44Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,168 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. C44S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 ENST00000357654.9 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:23 U:1 O:1
• Conservation: PhyloP100: 3.48

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 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in ENST00000357654.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43115730-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 54191.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 17-43115729-C-A is Pathogenic according to our data. Variant chr17-43115729-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 54200.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115729-C-A is described in Lovd as [Pathogenic]. Variant chr17-43115729-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.131G>T	p.Cys44Phe	missense_variant	3/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.131G>T	p.Cys44Phe	missense_variant	3/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461168 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726864

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8 Uncertain:1 Other:1

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	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 = 0.999964 -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 07, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces cysteine with phenylalanine at codon 44 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, ubiquitin E3 ligase, BARD1 binding, haploid cell proliferation and protein folding assays (PMID: 11573085, 20103620, 23161852, 25823446, 30209399; DOI:10.1158/2767-9764.CRC-21-0064). This variant has been reported in at least six individuals affected with breast and ovarian cancer (PMID: 16912212, 18159056, 22711857, 22713736, 28486781) and multiple suspected hereditary breast and ovarian cancer families (PMID: 12048272, 16267036, 19241424). This variant is also reported to have segregation and tumor pathology likelihood ratios for pathogenicity of 156.1745 and 41.2405, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	A known pathogenic variant was detected in the BRCA1 gene in this specimen. This sequence change replaces cysteine with phenylalanine at codon 44 of the BRCA1 protein (p.Cys44Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not found in gnomAD exomes. This variant has been reported in individuals affected with breast and or ovarian cancer (PMID: 23633455, 18159056, 25777348, 16267036). This variant is also known as 250G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54200) and classifies this variant as Pathogenic, rated 3 stars, reviewed by expert panel. Experimental studies have shown that this missense change disrupts several BRCA1 protein functions, including single-strand annealing and homology directed repair, regulation of centrosome duplication, BARD1 binding and ubiquitin ligase activity (PMID: 20103620, 16403807, 23161852, 21725363, 27272900). Therefore, this variant has been classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
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, criteria provided, single submitter	clinical testing	Counsyl	Feb 01, 2017	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 18, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant is a single amino acid change from Cysteine to Phenylalanine at amino acid residue 44 of the BRCA1 protein. The Cysteine residue is highly conserved among species and is located in a functional domain of the protein and a region known to interact with multiple proteins. There is a large physiochemical difference between Cysteine acid and Phenylalanine (Grantham Score 205). To our knowledge, this variant is not present in population databases (rs80357446). This variant is also known as c.250G>T in the literature and it was shown to disrupt normal protein function by a yeast two-hybrid E3 Ub-ligase activity assay, a homology directed recombination assay, a BARD1 binding assay and a centrosome amplification assay (PMID: 20103620, 21725363). In addition, several individuals with personal and/or family history consistent with Hereditary Breast and Ovarian Cancer syndrome were found to carry this variant (PMID: 22713736). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein. The mutation database Clinvar contains entries for this variant (Variation ID: 54200). -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 11, 2019	- -
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	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2022	Published functional studies demonstrate a damaging effect: disrupted homology-directed repair and BARD1 binding, and loss of E3 ubiquitin ligase activity and centrosome amplification (Morris 2006, Ransburgh 2010, Kais 2012, Starita 2015, Findlay 2018); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (John 2007, Hall 2009, Jalkh 2012, Lolas Hamameh 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons 2019); Also known as 250G>T; This variant is associated with the following publications: (PMID: 24312913, 26187060, 23161852, 16403807, 25823446, 28486781, 30350268, 15235020, 20103620, 11320250, 22713736, 12732733, 21725363, 23633455, 25085752, 25777348, 25814778, 18159056, 19241424, 27272900, 28202063, 28364669, 29446198, 30209399, 33087888, 31131967, 24389207, 20104584, 8944023) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Dec 17, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 44 of the BRCA1 protein (p.Cys44Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and or ovarian cancer (PMID: 16267036, 18159056, 23633455, 25777348). This variant is also known as 250G>T. ClinVar contains an entry for this variant (Variation ID: 54200). 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: 12732733, 16403807, 20103620, 21725363, 22843421, 23161852, 27272900). This variant disrupts the p.Cys44 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19543972, 21922593, 25823446, 27083775). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	Mar 07, 2018	Variant summary: BRCA1 c.131G>T (p.Cys44Phe) results in a non-conservative amino acid change located in the RING binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245760 control chromosomes (gnomAD). The variant, c.131G>T, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Alsop_2012, Jalkh_2012, El Saghir_2015, Christie_2017, etc). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies found that the variant significantly impacts proper BRCA1 protein function (Kais_2012, Morris_2006,Ransburgh_2010, Towler_2013, and Thouvenot_2016). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 17, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Nov 10, 2011	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 27, 2021	The p.C44F pathogenic mutation (also known as c.131G>T), located in coding exon 2 of the BRCA1 gene, results from a G to T substitution at nucleotide position 131. The cysteine at codon 44 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This mutation occurs in the functionally important RING finger domain (Abkevich V et al. J. Med. Genet. 2004 Jul;41:492-507). Based on internal structural assessment, this alteration is predicted to disrupt formation of zinc binding site 1 and overall folding of the BRCA1 protein. This is consistent with Brzovic PS et al (2010), who showed that experimentally altering ligands at this residue yields BRCA1 RING domains that fail to fold properly (Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8:833-7). Multiple functional studies have shown that this alteration is deleterious including a centrosome amplification assay, a homology directed repair assay, a single stranded annealing assay and a high throughput cell survival assay (Kais Z et al. Oncogene. 2012 Feb;31:799-804; Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Findlay GM et al. Nature, 2018 Sep;). This mutation has been identified in multiple breast and/or ovarian cancer families in the literature (Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63; Jalkh N et al. Hered Cancer Clin Pract. 2012 Jun;10:7; George J et al. Clin. Cancer. Res. 2013 Jul;19:3474-84; Lolas Hamameh S et al. Int. J. Cancer. 2017 Aug;141:750-756). In addition, two other alterations at the same codon, p.C44Y and p.C44S, have been classified as definitely pathogenic (p>0.99) by 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 DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2023	This missense variant replaces cysteine with phenylalanine at codon 44 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, ubiquitin E3 ligase, BARD1 binding, haploid cell proliferation and protein folding assays (PMID: 11573085, 20103620, 23161852, 25823446, 30209399; DOI:10.1158/2767-9764.CRC-21-0064). This variant has been reported in at least six individuals affected with breast and ovarian cancer (PMID: 16912212, 18159056, 22711857, 22713736, 28486781) and multiple suspected hereditary breast and ovarian cancer families (PMID: 12048272, 16267036, 19241424). This variant is also reported to have segregation and tumor pathology likelihood ratios for pathogenicity of 156.1745 and 41.2405, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

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

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;T;D;D;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;H;H;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.2	D;N;N;D;D;D;N;.;N;N;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		0.99, 0.97, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.87
MutPred		0.98		Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);
MVP		1.0
MPC		0.15
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80357446; hg19: chr17-41267746;