Submissions for variant NM_007294.4(BRCA1):c.4882A>G (p.Met1628Val)

gnomAD frequency: 0.00008  dbSNP: rs80357465

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130592	SCV000185465	likely benign	Hereditary cancer-predisposing syndrome	2018-06-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
CSER _CC_NCGL, University of Washington	RCV000148406	SCV000190105	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	RCV000212187	SCV000209979	likely benign	not specified	2017-03-01	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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130592	SCV000747798	likely benign	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000761958	SCV000892185	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130592	SCV000910925	likely benign	Hereditary cancer-predisposing syndrome	2015-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212187	SCV000916723	benign	not specified	2021-06-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4882A>G (p.Met1628Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4882A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer (example, Durocher_1996, Troudi_2007, Lu_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been observed in the UMD database and at our laboratory (UMD database-BRCA1 c.25G>T, p.Glu9*; our laboratory-BRCA1 c.4357+1G>A), providing supporting evidence for a benign role. Multiple publications report contradictory experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of transcriptional activation similar to a null allele (Phelan_2005), whereas another study evaluating transcriptional acitivity reported a neutral outcome (Frenandes_2019). Another assay measuring yeast colony size found no difference when compared to a WT control (Coyne_2004). Other reports have classified the variant as a VUS (Iversen_2011), as likely not pathogenic (Woods_2016) based on functional studies.. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus leaning towards likely benign (n=6)/benign (n=1) and one submitter reporting a VUS outcome. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000761958	SCV001133597	likely benign	not provided	2019-04-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000112414	SCV001140507	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001474576	SCV001678747	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212187	SCV002069973	likely benign	not specified	2019-12-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4882A>G, in exon 15 that results in an amino acid change, p.Met1628Val. This sequence change has been described in the gnomAD database with a frequency of 0.004% in European populations (dbSNP rs80357465). The p.Met1628Val change has been identified in one individual with breast and/or ovarian cancer (PMID: 8776600). The p.Met1628Val change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Met1628Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies demonstrated about 80% of the wild-type protein activity, suggesting this is a neutral variant (PMID: 17311832). We classify this sequence change as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000761958	SCV003799772	likely benign	not provided	2022-03-23	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112414	SCV000145200	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	RCV001353677	SCV000591544	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Met1628Val variant has been previously reported in the literature in 2/40128 proband chromosomes of individuals with breast cancer. However, no controls were tested to establish the frequency of the variant in the general population (Abkevich_2004_15235020, Iversen_2011_21447777, Phelan_2005_15689452, Carvalho_2007_17308087, Tamboom_2010_20380699). Functional studies have reported that the variant displayed ~80% of the wild-type activity, suggesting that it corresponds to a neutral variant (Phelan_2005_15689452, Carvalho_2007_17308087). The variant has been reported in the UMD (x3), BIC (6x with unknown clinical importance), dbSNP (ID:rs80357465) and the Exome Variant Server (frequency: 0.0002) and CNPHI (ACMG3) databases. In the UMD database, the variant was observed to co-occur with another BRCA1 pathogenic mutation: BRCA1: c.25G>T (p.Glu9X), increasing the likelihood that the p.Met1628Val variant does not have any clinical significance. This residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. In addition, the variant amino acid valine (Val) is present in the mouse at this position, increasing the likelihood that an alteration to this residue may not have functional significance. However, this information is not predictive enough to rule out pathogenicity. It should be noted that although this variant occurs outside of the splicing consensus sequence, in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 2 of 5 different programs. However, this information is not predictive enough to determine the clinical significance of this variant. 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. The p.Met1628Val variant is classified as predicted benign.