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

gnomAD frequency: 0.00007  dbSNP: rs56039126

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)	RCV000111700	SCV000244309	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 = 0.0000212
Invitae	RCV000167782	SCV000075623	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	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	RCV001353432	SCV000209932	likely benign	not provided	2020-09-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25637381, 18703817, 18284688, 21520273, 17990525, 23231788, 18273839, 23893897, 26898890, 9663595, 21990134, 17924331, 25682074, 20104584, 16267036, 15385441, 19370767, 33087888)
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, susceptibility to, 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, Mass General Brigham 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 Diagnostics, LLC DBA Color Health	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, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000111700	SCV001285070	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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.
Sema4, Sema4	RCV000162564	SCV002538057	likely benign	Hereditary cancer-predisposing syndrome	2021-01-23	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001353432	SCV003917928	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	BRCA1: BP1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000047610	SCV004026798	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111700	SCV000144203	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000047610	SCV001905978	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000047610	SCV001959165	benign	not specified		no assertion criteria provided	clinical testing