ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4993G>A (p.Val1665Met) (rs80357169)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080706 SCV000076745 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129500 SCV000184272 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Structural Evidence
GeneDx RCV000420335 SCV000516131 likely benign not specified 2017-12-21 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 RCV000048732 SCV000605898 likely benign not provided 2019-06-07 criteria provided, single submitter clinical testing
Counsyl RCV000083214 SCV000785227 uncertain significance Breast-ovarian cancer, familial 1 2017-06-21 criteria provided, single submitter clinical testing
GeneKor MSA RCV000129500 SCV000821927 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129500 SCV000909002 likely benign Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000420335 SCV001361835 likely benign not specified 2019-04-01 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4993G>A (p.Val1665Met) results in a conservative amino acid change located in the BRCT domain of 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 1.6e-05 in 246102 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance; the possibility of the variant being a rare polymorphism cannot be excluded. c.4993G>A has been reported in the literature in breast and/or ovarian cancer families and was noted to not segregate with disease in at least one reported family (Azzollini_2016, Claes_2004). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported in the BIC database (BRCA2 c.1754delA, p.Lys585fsX29; BRCA2 c.2830A>T, p.Lys944X), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to have no functional effect and to display wild-type activity (Findlay_2018, Lee_2010, Vallon-Christersson_2001). Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (3x) and as uncertain significance (3x). Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000083214 SCV000115288 likely benign Breast-ovarian cancer, familial 1 2012-03-26 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083214 SCV000145256 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000083214 SCV001243901 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000083214 SCV001551184 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Val1665Met variant was identified in 2 of 4406 proband chromosomes (frequency: 0.0005) from individuals or families with breast and ovarian cancer (Azzollini 2016, Claes 2004). It was also identified in dbSNP (ID: rs80357169) as "With Uncertain significance, other allele", in ClinVar (classified 5x as Likely benign by GeneDx, Invitae, Ambry Genetics, SCRP and one other submitter and 4x Uncertain significance by submitters), LOVD 3.0 (observed 5x), UMD-LSDB (8 records of unknown clinical significance) and in the BIC Database (4x unknown clinical importance). The variant was identified in control databases in 4 of 246102 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33580 chromosomes (freq: 0.00003), European in 3 of 111586 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. rnA range of functional, evolutionary, biochemical and computational studies have involved the variant with conflicting interpretations. Transcriptional assay studies demonstrated the variant displayed similar activity to wild-type controls in both yeast and mammalian cells, suggesting a “benign polymorphism” (Vallon-Christersson 2001). No functional effect of the variant was also demonstrated in another study that looked at protein folding, peptide biding activity and specificity and transcriptional activity in human cells in comparison to the wild-type control (Lee 2010). A biophysical study measuring thermodynamic stability of the BRCA1 BRCT domains classified the variant as “mildly destabilizing” protein folding when compared to the wild-type (Rowling 2010). Two computational studies also had conflicting variant classifications of “neutral” and as a “variant of unknown significance” (Karchin 2007, Iversen 2011). The p.Val1665 residue is 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. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.

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