ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2315T>C (p.Val772Ala) (rs80357467)

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Total submissions: 23
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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 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
Invitae RCV001080314 SCV000075810 benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
Counsyl RCV000111824 SCV000154018 likely benign Breast-ovarian cancer, familial 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: 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 1 2016-04-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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 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 Health, Inc RCV000162790 SCV000683027 likely benign Hereditary cancer-predisposing syndrome 2015-01-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 1 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000111824 SCV000744662 benign Breast-ovarian cancer, familial 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 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000111824 SCV001283970 likely benign Breast-ovarian cancer, familial 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 2017-11-20 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 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 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

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