ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1865C>T (p.Ala622Val) (rs56039126)

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Total submissions: 14
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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) RCV000111700 SCV000244309 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 = 0.0000212
Invitae RCV000167782 SCV000075623 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148408 SCV000190107 uncertain significance Breast neoplasm 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000047610 SCV000209932 likely benign not specified 2017-07-24 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 RCV000162564 SCV000212977 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 RCV000111700 SCV000267694 likely benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768617 SCV000324824 uncertain significance Breast and/or ovarian cancer 2015-08-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000047610 SCV000538450 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: Multple papers describe as VUS; ClinVar: 2 B/LB, 3 VUS
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047610 SCV000698893 benign not specified 2019-03-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1865C>T (p.Ala622Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 276900 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.5e-05 vs 0.001), allowing no conclusion about variant significance. c.1865C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, however, with limited information (ie, lack of co-occurrence and/or cosegregation data)(Tikhomirova_2007, Wagner_1998, Moghadasi_2013, Anczukow_2008, Borg_2010, Judkins_2005, Lee_2008, Palma_2008, Wong-Brown_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other likely pathogenic/pathogenic variants have been reported (BRCA2 c.5722_5723delCT, p.Leu1908Argfs; BRCA2 c.658_659delGT, p.Val220Ilefs; BRCA2 c.6275_6276delTT, p.Leu2092Profs; BRIP1 c.440dupA, p.Tyr147X), providing supporting evidence for a benign role. Variant was functionally assessed to have no impact on splicing (Anczukow_2008). Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant four times as likely benign/benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Color Health, Inc RCV000162564 SCV000902725 likely benign Hereditary cancer-predisposing syndrome 2020-04-17 criteria provided, single submitter clinical testing
Mendelics RCV000111700 SCV001140593 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000111700 SCV001285070 uncertain significance Breast-ovarian cancer, familial 1 2017-04-27 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111700 SCV000144203 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353432 SCV000591354 likely benign not provided no assertion criteria provided clinical testing The BRCA1 p.Ala622Val variant was identified in 5 of 26494 proband chromosomes (frequency: 0.0002) from individuals or families with breast and ovarian cancer and was present in 2 of 38,284 control chromosomes (frequency: 0.00005) from healthy individuals (Wong-Brown 2015, Moghadasi 2013, Momozawa 2018, Borg 2010, Lee 2008, Tikhomirova 2007). The variant was identified in dbSNP (rs56039126) as “with other allele”, ClinVar (classified as benign by Invitae, Color, Integrated Genetics, Ambry Genetics and ENIGMA, uncertain significance by Partners Healthcare, BIC and 2 other submitters and likely benign by GeneDx and University of Michigan), LOVD 3.0 (observed 1x) and UMD-LSDB (observed 14x). The variant was identified in control databases in 15 of 267,978 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 13 of 117,956 chromosomes (freq: 0.0001), East Asian in 1 of 19,248 chromosomes (freq: 0.00005), Latino in 1 of 35,080 chromosomes (freq: 0.00003); it was not observed in the African, Ashkenazi Jewish, Finnish, Other and South Asian populations. A clinical laboratory reported that the variant was identified with multiple co-occurring pathogenic variants (BRCA2 c.5722_5723delCT; p.Leu1908Argfs, BRCA2 c.658_659delGT; p.Val220Ilefs, BRCA2 c.6275_6276delTT; p.Leu2092Profs, BRIP1 c.440dupA; p.Tyr147*). In addition, the variant had no demonstrated effect on in vitro splicing (Anczukow 2008). The p.Ala622Val residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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