Submissions for variant NM_007294.4(BRCA1):c.5138T>C (p.Val1713Ala)

dbSNP: rs80357132

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048808	SCV000076821	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-19	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 55412). 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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17305420, 17308087, 20516115, 21447777, 30209399). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 7611277, 25556971; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1713 of the BRCA1 protein (p.Val1713Ala). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl	RCV000112502	SCV000786490	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-05-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000733369	SCV000861432	uncertain significance	not provided	2018-05-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000733369	SCV000883462	uncertain significance	not provided	2018-05-21	criteria provided, single submitter	clinical testing	The BRCA1 c.5138T>C; p.Val1713Ala variant (rs80357132) is described in the literature in a proband with breast and ovarian cancer, as well as a strong family history of breast and ovarian cancer (Struewing 1995). Functional analyses suggest the variant causes altered substrate binding and specificity as well as altered transcriptional activity (Carvalho 2007, Lee 2010). This variant is reported in ClinVar (Variation ID: 55412). It is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 1713 is highly conserved and computational analyses (SIFT, PolyPhen2) predict that this variant may be deleterious. However, due to limited information, the clinical significance of the p.Val1713Ala variant is uncertain at this time. REFERENCES Carvalho MA et al. Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. Cancer Res. 2007 Feb 15;67(4):1494-501. Lee MS et al. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res. 2010 Jun 15;70(12):4880-90. Struewing JP et al. Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer. Am J Hum Genet. 1995 Jul;57(1):1-7.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048808	SCV000916764	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5138T>C (p.Val1713Ala) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251322 control chromosomes. c.5138T>C has been reported in the literature in individuals from large families affected with Hereditary Breast and Ovarian Cancer, however without evidence of co-segregation to support causality (e.g. Struewing_1995, Humphrey_1997, Trujillano_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple publications report experimental evidence evaluating an impact on protein function. For example, the variant has been reproducibly reported to reduce BRCA1 transactivation activity (Carvalho_2007, Lee_2010, Woods_2016) and phosphopeptide binding /specificity (Lee_2010). This variant has been cited as a "hypomorphic variant" in the literature (Woods_2016). The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 20516115, 14534301, 9159158, 17308087, 7611277, 18992264, 24845084, 25556971, 21309043, 28781887, 30765603, 21447777). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n= 7; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV001023598	SCV001185500	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-30	criteria provided, single submitter	clinical testing	The p.V1713A variant (also known as c.5138T>C), located in coding exon 16 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5138. The valine at codon 1713 is replaced by alanine, an amino acid with similar properties. This alteration was seen in a proband with breast and ovarian cancer. This individual's family history was significant for breast and ovarian cancer, but co-segregation could not be established due to family members being deceased (Struewing JP et al. Am. J. Hum. Genet., 1995 Jul;57:1-7). Multiple transcriptional activation functional studies classified this variant as functionally deleterious (Findlay GM et al. Nature, 2018 10;562:217-222; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev., 2011 Jun;20:1078-88; Karchin R et al. PLoS Comput. Biol., 2007 Feb;3:e26; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69; Woods NT et al. NPJ Genom Med, 2016 Mar). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). V1713A destabilizes the structure as much as other pathogenic variants nearby (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000733369	SCV002069180	likely pathogenic	not provided	2018-05-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000733369	SCV004026753	likely pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000733369	SCV005201800	likely pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: classified as non-functional based on transcriptional activity, binding activity and specificity, and cell survival (PMID: 17308087, 20516115, 30209399, 30765603, 35665744); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individual(s) with breast and ovarian cancer (PMID: 9159158); Also known as 5257T>C; This variant is associated with the following publications: (PMID: 21447777, 20516115, 17305420, 7611277, 17308087, 28781887, 25556971, 30209399, 30765603, 30257991, 35665744, 14534301, 18992264, 25652403, 25348405, 9159158, 16267036)
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112502	SCV000145324	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-07-10	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112502	SCV001243610	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000733369	SCV001978711	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000733369	SCV001979402	likely pathogenic	not provided		no assertion criteria provided	clinical testing