rs80357508

Positions:

• chr17-43091462-CTTGA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000357654.9(BRCA1):​c.4065_4068del​(p.Asn1355LysfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: BRCA1 ENST00000357654.9 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:52
• Conservation: PhyloP100: 3.20

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-43091462-CTTGA-C is Pathogenic according to our data. Variant chr17-43091462-CTTGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 17674.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091462-CTTGA-C is described in Lovd as [Pathogenic]. Variant chr17-43091462-CTTGA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4065_4068del	p.Asn1355LysfsTer10	frameshift_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4065_4068del	p.Asn1355LysfsTer10	frameshift_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152222 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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250844 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: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461326 Hom.: 0 AF XY: 0.0000385 AC XY: 28 AN XY: 726950

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

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: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:52

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:23

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 17, 2022	The BRCA1 c.4065_4068del variant is classified as Pathogenic (PVS1, PS4_Supporting, PM2) This BRCA1 c.4065_4068del variant is located in exon 10/23 and is predicted to cause a shift in the reading frame at codon 1355. The variant is rare in population databases (PM2). The variant has been reported in dbSNP (rs80357508) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 17674). It has not been reported in HGMD. BRCA1:c.4065_4068del (also described as BRCA1 4184del4 using legacy nomenclature) has been reported in multiple unrelated individuals and families with breast, peritoneal, fallopian tube and ovarian cancer (Siraj et al., 2018 PMID: 30825404, Singh et al., 2018 PMID: 29470806; Heramb et al., 2018 PMID: 29339979; Li et al., 2019 PMID: 29752822). -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PVS1+PS4_Moderate+PM2_Supporting -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 14, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	A known pathogenic mutation was detected in the BRCA1 gene in this specimen. This sequence change creates a premature translational stop signal (p.Asn1355Lysfs*10) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 14757871, 8571953, 11802209, 21559243). This variant is also known as 4184del4 in the literature. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.4065_4068del (p.Asn1355LysfsTer10) frameshift variant in BRCA1 gene has been reported previously in multiple individuals and families affected with breast and ovarian cancer (Farooq et al., 2011; Meindl, 2002). The p.Asn1355LysfsTer10 variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Asparagine 1355, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Asn1355LysfsTer10. Loss-offunction variants in BRCA1 are known to be pathogenic (Borg et al., 2010). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 17, 2023	Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS4_STR -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 21, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1994	- -
Pathogenic, criteria provided, single submitter	research	Institute of Genomics, University of Tartu	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 06, 2021	PVS1, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Bioinformatics dept., Datar Cancer Genetics Limited, India	Jul 21, 2017	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 19, 2017	- -
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	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	BRCA1: PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2023	The BRCA1 c.4065_4068delTCAA; p.Asn1355LysfsTer10 variant (rs80357508), also known as 4184_4187del4, is reported in the literature in multiple individuals and families with breast and ovarian cancer (Evans 2004, Farooq 2011, Friedman 1994, George 2013, Leongamornlert 2014, Li 2019, Meindl 2002, Neuhausen 1996, Zhang 2011). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 17674), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Evans DG et al. Haplotype and cancer risk analysis of two common mutations, BRCA1 4184del4 and BRCA2 2157delG, in high risk northwest England breast/ovarian families. J Med Genet. 2004 Feb;41(2):e21. PMID: 14757871. Farooq A et al. Breast and Ovarian Cancer Risk due to Prevalence of BRCA1 and BRCA2 Variants in Pakistani Population: A Pakistani Database Report. J Oncol. 2011;2011:632870. PMID: 21559243. Friedman LS et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet. 1994 Dec;8(4):399-404. PMID: 7894493. George J et al. Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. Clin Cancer Res. 2013 Jul 1;19(13):3474-84. PMID: 23633455. Leongamornlert D et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer. 2014 Mar 18;110(6):1663-72. PMID: 24556621. Li JY et al. Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. Int J Cancer. 2019 Jan 15;144(2):281-289. PMID: 29752822. Meindl A et al. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 2002 Feb 1;97(4):472-80. PMID: 11802209. Neuhausen SL et al. Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet. 1996 Feb;58(2):271-80. PMID: 8571953. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. PMID: 21324516. -
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	Mayo Clinic Laboratories, Mayo Clinic	Aug 08, 2022	PP5, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 13, 2023	This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer and ovarian cancer in the published literature (PMIDs: 29752822 (2018), 29470806 (2018), 28993434 (2018), 27553291 (2016), 28831036 (2017)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in many individuals with personal and/or family history consistent with pathogenic variants in this gene (Friedman 1994, Neuhausen 1996, Liede 2002, Meindl 2002, Farooq 2011, Couch 2015, Bu 2016, Chan 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 23633455, 24556621, 21559243, 11802209, 10699917, 26852015, 20104584, 25948282, 31957001, 25085752, 29348823, 29752822, 31372034, 30199306, 7894493, 8571953, 12181777, 25452441, 27082205, 30093976, 24504028, 2270482, 21324516, 17018160, 14757871, 23683081, 23175448, 24549055, 7894492, 8531967, 27157322, 16455195, 26997744, 26350514, 28127413, 27836010, 27553291, 28392550, 29907814, 29422015, 7837387, 28831036, 17100994, 29339979, 29470806, 28724667, 28993434, 30702160, 30078507, 28176296, 30720243, 30014164, 31174498, 30322717, 30825404, 31454914, 31528241, 29625052, 26689913, 29176636, 32029870, 31948886) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 15, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Asn1355LysfsX10 variant in BRCA1 has been reported in >100 individuals with BRCA1-associated cancers (Friedman 1994 PMID:7894493, Zhang 2011 PMID:21324516, George 2013 PMID:23633455, Cao 2013 PMID:23175448, Cunningham 2014 PMID:24504028, Leongamornlert 2014 PMID:24556621, Rashid 2016 PMID:27553291, Sun 2017 PMID:28724667, Maxwell 2017 PMID:28831036, Hirasawa 2017 PMID:29348823, Li 2018 PMID:30078507, Singh 2018 PMID:29470806, Wen 2018 PMID:28993434, Li 2019 PMID:29752822, Breast Information Core Database (BIC): https://research.nhgri.nih.gov/bic/). It has also been identified in 0.004% (3/68040) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1355 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 17674). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2017	Variant summary: The BRCA1 c.4065_4068delTCAA (p.Asn1355Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.4117G>T, p.Glu1373X; c.4158_4162delCTCTC, p.Ser1387fs). This variant has been reported in numerous HBOC patients with positive family history (e.g. Langston 1996, Spitzer 2000, Evans 2004, Borg 2010). This variant is absent in 121322 control chromosomes, suggesting that it is not a common, benign variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Asn1355Lysfs*10) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357508, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 8571953, 11802209, 14757871, 21559243). It has also been observed to segregate with disease in related individuals. This variant is also known as 4184del4. ClinVar contains an entry for this variant (Variation ID: 17674). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 01, 2017	- -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Breast and/or ovarian cancer Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 25, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 08, 2010	- -
Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Jun 11, 2019	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 28, 2022	The c.4065_4068delTCAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 4065 to 4068, causing a translational frameshift with a predicted alternate stop codon (p.N1355Kfs*10). This alteration has been reported in multiple families with hereditary breast and ovarian cancer from a variety of ethnic backgrounds (Shattuck-Eidens D et al. JAMA. 1995 Feb;273:535-41; Langston AA et al. N. Engl. J. Med. 1996 Jan;334:137-42; Spitzer E et al. Int. J. Cancer. 2000 Feb;85:474-81; Ahn SH et al. Cancer Lett. 2007 Jan;245:90-5; Cunningham J et al. Sci. Rep. 2014 Feb;4:4026; Rashid MU et al. BMC Cancer. 2016 Aug;16:673; Li JY et al. Int. J. Cancer 2019 Jan;144(2):281-289; Siraj AK et al. Hum. Mutat. 2019 Mar). This mutation was also identified in an individual from a cohort of 191 prostate cancer patients with at least three prostate cancer cases in their families; this individual's family was also noted to be affected with breast and colon cancer (Leongamornlet D et al. Br. J. Cancer. 2014 Mar;110:1663-72). Of note, this alteration is also designated as 4184del4 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2023	This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This is a recurrent variant detected in hereditary breast and ovarian cancer families worldwide and has been reported in at least 30 individuals affected with breast and/or ovarian cancer (PMID: 7894493, 8531967, 17018160, 16455195, 20104584, 21324516, 21559243, 23175448, 23633455, 27553291, 28724667, 28831036, 28993434, 29470806, 30078507, 29752822, 30825404, 33471991; Leiden Open Variation Database DB-ID BRCA1_000288) and an individual affected with prostate cancer (PMID: 24556621). This variant has been identified in 3/250844 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -
Pathogenic, no assertion criteria provided	literature only	Center for Precision Medicine, Meizhou People's Hospital	-	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneKor MSA

Jul 01, 2016

- -

Inherited breast cancer and ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Aug 15, 2024

PVS1,PM5_Strong -

BRCA1-related cancer predisposition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 28, 2024

This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This is a recurrent variant detected in hereditary breast and ovarian cancer families worldwide and has been reported in at least 30 individuals affected with breast and/or ovarian cancer (PMID: 7894493, 8531967, 17018160, 16455195, 20104584, 21324516, 21559243, 23175448, 23633455, 27553291, 28724667, 28831036, 28993434, 29470806, 30078507, 29752822, 30825404, 33471991; Leiden Open Variation Database DB-ID BRCA1_000288) and an individual affected with prostate cancer (PMID: 24556621). This variant has been identified in 3/250844 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). 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

Apr 14, 2022

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Asn1355LysfsX10 variant was identified in 7 of 7698 proband chromosomes (frequency: 0.0009) from individuals or families with breast, ovarian, and prostate cancer and was not identified in 3994 control chromosomes from healthy individuals (Leongamornlert 2014, George 2013, Cao 2013, Alvarez 2017, Hoberg-Vetti 2016, Rashid 2016, Thompson 2016). The variant was also identified in the following databases: dbSNP (ID: rs80357508) as “With Pathogenic allele”, ClinVar (18x pathogenic including review by expert panel ENIGMA, 1x likely pathogenic), LOVD 3.0 (23x), UMD-LSDB (88x, causal), and the BIC Database (144x pathogenic). The variant was not identified in Cosmic, MutDB, or the Zhejiang University Database. In addition, the variant was identified by our laboratory in two individuals with breast cancer. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (Feb 27, 2017). The c.4065_4068delTCAA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1355 and leads to a premature stop codon at position 1364. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs80357508; hg19: chr17-41243479;