Submissions for variant NM_007294.4(BRCA1):c.2315T>C (p.Val772Ala)

gnomAD frequency: 0.00012  dbSNP: rs80357467

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111824	SCV000244316	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000000192
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080314	SCV000075810	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000111824	SCV000154018	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-02-06	criteria provided, single submitter	literature only
GeneDx	RCV000168496	SCV000167254	benign	not specified	2014-01-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000162790	SCV000213268	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000111824	SCV000267700	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168496	SCV000538449	uncertain significance	not specified	2016-06-16	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple papers describe as VUS; ClinVar: 5 B/LB, 3 VUS
Fulgent Genetics, Fulgent Genetics	RCV000111824	SCV000575713	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168496	SCV000593674	likely benign	not specified	2017-05-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162790	SCV000683027	likely benign	Hereditary cancer-predisposing syndrome	2015-01-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000034731	SCV000708437	uncertain significance	not provided	2017-05-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000111824	SCV000743418	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000111824	SCV000744662	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000168496	SCV000883464	benign	not specified	2018-12-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000111824	SCV001140576	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000111824	SCV001283970	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-03-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170822	SCV001333440	likely benign	Breast and/or ovarian cancer	2023-06-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162790	SCV002538108	likely benign	Hereditary cancer-predisposing syndrome	2021-01-04	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000034731	SCV002545931	benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	BRCA1: BS1, BS2
All of Us Research Program, National Institutes of Health	RCV000111824	SCV004818201	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034731	SCV000043177	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111824	SCV000144378	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148397	SCV000190096	uncertain significance	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353867	SCV000591379	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Val772Ala variant was identified in at least 22 of 112026 proband chromosomes from individuals with breast or ovarian cancer, or who were undergoing BRCA1 screening (Castilla 1994, Haffty 2009, Judkins 2005); however, control chromosomes were not included in these studies, thus the frequency of the variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs80357467) “With allele of Uncertain significance”, HGMD, LOVD, UMD (8X as a neutral variant), and the BIC database (60X with unknown clinical importance). The variant was identified in two of 8600 European American alleles in the NHLBI Exome Sequencing Project (Exome Variant Server), although the limited number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population. This residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The p.Val772Ala has been identified in the literature occurring in trans with known deleterious mutations in BRCA1, increasing the likelihood that it does not have clinical significance (Castilla 1994, Judkins 2005, Spearman 2008, Tavtigian 2006). In addition, four in silico studies have classified this variant as not pathogenic or neutral (Burk-Herrick 2005, Lee 2008, Lindor 2012, Spearman 2008, while another study left the variant as “unclassified” (Tavtigian 2006). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000111824	SCV000733645	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034731	SCV000778758	likely benign	not provided	2017-05-17	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168496	SCV001905747	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168496	SCV001956923	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001080314	SCV001977030	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-09-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554641	SCV004765954	likely benign	BRCA1-related disorder	2022-12-15	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).