ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4837A>T (p.Ser1613Cys) (rs1799966)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079703 SCV000076686 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130704 SCV000185591 likely benign Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
GeneDx RCV000048673 SCV000209977 likely benign not specified 2017-05-12 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589264 SCV000605893 benign not provided 2019-04-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130704 SCV000683220 likely benign Hereditary cancer-predisposing syndrome 2016-10-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048673 SCV000699177 likely benign not specified 2020-10-09 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4837A>T (p.Ser1613Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251384 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American 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 Syndrome (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.4837A>T has been reported in the literature in individuals affected with Breast And Ovarian Cancer Syndrome (Majdak_2005, DArgenio_2015, Cifuentes-C_2019, Cecener_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant is likely not pathogenic (Woods_2016, Fernandes_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000031194 SCV000053794 benign Breast-ovarian cancer, familial 1 2011-11-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031194 SCV000145194 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354846 SCV001549558 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Ser1613Cys variant was identified in 1 of 140 proband chromosomes (frequency: 0.007) from individuals or families with breast cancer (D'Argenio 2015). The variant was also identified in dbSNP (rs1799966) as “other”, in ClinVar with conflicting interpretations of pathogenicity (5 submitters, classified as Likely Benign by Invitae, Ambry, and GeneDx, classified as Uncertain Significance by BIC and as Benign by the Sharing Clinic Reports Project), in Clinvitae (classified as Likely benign as reported in ClinVar) and in BIC (4x classified as unknown), the Fanconi Anemia Mutation Database (3x classified as predicted neutral) databases. The variant was also identified in the control database the Exome Aggregation Consortium (ExAC) in 8 of 121360 chromosomes (freq. 0.00007), all cases were seen in the African population specifically 8 of 10406 chromosomes (freq. 0.0008), increasing the likelihood that this may be a low frequency benign variant. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the ARUP Laboratories BRCA Mutations Database, COSMIC, GeneInsight COGR, and UMD. Functional studies initially reported the p.Ser1613Cys variant to be disease causing based on a transcription activation assay performed in yeast (Monteiro 1997). However a more recent and more sensitive transcriptional assay reported the p.Ser1613Cys variant to be likely neutral and noted that the sensitivity of the previous assay was likely the reason for the conflicting results (Carvalho 2009). The p.Ser1613 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Moreover this locus is the known site of a common polymorphism in BRCA1 p.Ser1613Gly (identified in 35% of cases in ExAC) and classified as Benign by our laboratory. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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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