Submissions for variant NM_007294.4(BRCA1):c.5137del (p.Trp1712_Val1713insTer)

dbSNP: rs80357997

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077601	SCV000300209	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000048807	SCV000076820	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1713*) 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 (rs80357997, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and male breast cancer (PMID: 7611277, 16683254, 25948282, 26976419, 27767231). It has also been observed to segregate with disease in related individuals. This variant is also known as 5256delG. ClinVar contains an entry for this variant (Variation ID: 55411). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131392	SCV000186368	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	clinical testing	The c.5137delG pathogenic mutation, located in coding exon 16 of the BRCA1 gene, results from a deletion of one nucleotide at position 5137. This changes the amino acid from a valine to a stop codon (p.V1713*). This mutation (designated as 5256delG) has been reported in multiple cohorts of breast and/or ovarian cancer families, including in a male affected with both breast and prostate cancer; in an ovarian cancer patient whose tumor showed loss-of-heterozygosity; in 3 Dutch families and a Polish family with a history of breast and ovarian cancer; and in a female with breast cancer diagnosed at 31 who also had a family history of breast cancer, among other cancers (Struewing J et al. Am J Hum Genet. 1995 Jul;57(1):1-7; Weren RD et al. Hum. Mutat., 2017 Feb;38:226-235; van der Hout AH et al. Hum. Mutat., 2006 Jul;27:654-66; Kluska A et al. BMC Med Genomics, 2015 May;8:19; Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). 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.
GeneDx	RCV000235540	SCV000292526	pathogenic	not provided	2023-09-06	criteria provided, single submitter	clinical testing	Nonsense 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 individuals with BRCA1-related cancers (Struewing et al., 1995; Meindl et al., 2002; Monnerat et al., 2007; Lee et al., 2011; Kluska et al., 2015; Tung et al., 2016; Weren et al., 2016; Chan et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5135delG, 5254delG, and 5256delG; This variant is associated with the following publications: (PMID: 22010008, 27767231, 17624602, 16267036, 25948282, 26843898, 28152038, 26976419, 30093976, 11802209, 7611277, 29625052, 30875412, 30787465, 26689913, 28888541, 29922827, 11597388, 15026808)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000077601	SCV000296274	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-12-15	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077601	SCV000326166	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048807	SCV000605766	pathogenic	Hereditary breast ovarian cancer syndrome	2017-03-01	criteria provided, single submitter	clinical testing	The p.Val1713X variant in BRCA1 has been reported in >15 individuals with BRCA1- associated cancers and segregated with disease in >7 affected relatives (Struewi ng 1995, Monnerat 2007, Breast Cancer Information Core (BIC) database). It was a lso identified in 1/66198 European chromosomes by the Exome Aggregation Consorti um (ExAC, http://exac.broadinstitute.org; dbSNP rs80357997); however, this frequ ency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is a deletion of a single nucleotide, which generates a premature termination codon at position 17 13, which is predicted to lead to a truncated or absent protein. Heterozygous lo ss of function of the BRCA1 gene is an established disease mechanism in HBOC. Fu rthermore, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300209.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Counsyl	RCV000077601	SCV000677658	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-29	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131392	SCV000679697	pathogenic	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077601	SCV000744597	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131392	SCV000911169	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 17 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with breast and ovarian cancer (PMID: 7611277, 11139249, 11802209, 16683254, 17624602, 23192404, 25452441, 25948282, 26976419, 27767231, 30093976) and this variant co-segregated with breast and ovarian cancer in one family (PMID: 7611277). This variant has been identified in 1/251322 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048807	SCV001467835	pathogenic	Hereditary breast ovarian cancer syndrome	2020-12-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5137delG (p.Val1713X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-06 in 251322 control chromosomes (gnomAD). c.5137delG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Struewing_1995, Vaziri_2001, Verhoog_2001, Judkins_2005, Couch_2015, Kluska_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000077601	SCV004215031	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000235540	SCV004224794	pathogenic	not provided	2022-03-08	criteria provided, single submitter	clinical testing	PP5, PM2, PVS1
Sharing Clinical Reports Project (SCRP)	RCV000077601	SCV000109404	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077601	SCV000145323	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048807	SCV000587469	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077601	SCV000733597	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358018	SCV001553649	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing