ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2083G>T (p.Asp695Tyr) (rs28897681)

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Total submissions: 10
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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) RCV000083177 SCV001161505 benign Breast-ovarian cancer, familial 1 2019-06-18 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 = 0.000263
Invitae RCV000047706 SCV000075719 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000166737 SCV000217548 likely benign Hereditary cancer-predisposing syndrome 2019-01-08 criteria provided, single submitter clinical testing Other strong data supporting benign classification
GeneDx RCV000430793 SCV000512291 likely benign not specified 2017-03-20 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.
Color Health, Inc RCV000166737 SCV000903863 likely benign Hereditary cancer-predisposing syndrome 2016-03-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000430793 SCV000918729 likely benign not specified 2018-04-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2083G>T (p.Asp695Tyr) 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 4.7e-05 in 276880 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.7e-05 vs 1.00e-03), allowing no conclusion about variant significance. This variant, c.2083G>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lu_2012, Anczukow_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1: c.5266dup (p.Gln1756ProfsX74) and c.3760A (p.Lys1254X); BRCA2: c.145G>T (p.Glu49X), c.5350_5351delAA (p.Asn1784HisfsX2), and c.1800T>G (p.Tyr600X)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified this variant as likely benign (2x) and VUS (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000083177 SCV001140585 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083177 SCV000115251 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083177 SCV000144296 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 RCV001353684 SCV000591369 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Asp695Tyr variant was identified in dbSNP (ID: rs28897681), LOVD, BIC (2X with unknown clinical importance), and UMD (19X as an unclassified variant). In the UMD database, this variant was identified in two samples with a second pathogenic BRCA2 or BRCA1 mutation (BRCA 1 c.3760A>T (p.Lys1254X) and BRCA2 c.5350 5351delAA (p.Asn1784HisfsX2)), increasing the likelihood that this variant does not have clinical significance. The variant was listed in the NHLBI Exome Sequencing project; however it was identified in only one out of 8600 tested European American chromosomes (frequency: 0.0001). The p.Asp695 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Three studies predict the variant to affect protein function or confer high risk; however, these predictions are based solely on evolutionary conservation analyses (Burk-Herrick 2006, Fleming 2003, Ramirez 2004). In the HGMD and BIC databases, another variant (c.2083G>A, p.D695N) was also listed with unknown clinical significance, and Greenman (1998) suggests that it may be a polymorphism. In summary, 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 predicted benign.

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