ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.946A>G (p.Ser316Gly) (rs55874646)

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Total submissions: 13
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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) RCV000031290 SCV001161601 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 = 2.21E-06
Invitae RCV000049198 SCV000077211 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130474 SCV000185340 likely benign Hereditary cancer-predisposing syndrome 2018-11-05 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768649 SCV000324825 uncertain significance Breast and/or ovarian cancer 2019-04-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031290 SCV000403073 uncertain significance Breast-ovarian cancer, familial 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000432519 SCV000512283 likely benign not specified 2017-11-27 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.
Counsyl RCV000031290 SCV000785231 uncertain significance Breast-ovarian cancer, familial 1 2017-06-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130474 SCV000902799 benign Hereditary cancer-predisposing syndrome 2015-11-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000432519 SCV000916801 likely benign not specified 2018-09-17 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.946A>G (p.Ser316Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five 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 277152 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 0.001), allowing no conclusion about variant significance. The variant, c.946A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Lee_2008, Azzollini_2016). These report(s) 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 UMD database (BRCA1 c.3228_3229delAG, p.Gly1077ALafsX8; BRCA2 c.6209_6212delAAAG, p.Glu2070ValfsX10), providing supporting evidence for a benign role. Multiple functional studies showed no impact on splicing, no sensitivity increase to ionizing radiation and an HDR assay showed no significant changes from wild-type (Anczukow_2008, Cochran_2015, Lu_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS x3, likely benign x2, benign x1). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284305 SCV001470016 likely benign not provided 2020-06-26 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031290 SCV000053895 benign Breast-ovarian cancer, familial 1 2009-03-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031290 SCV000143958 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 RCV001353805 SCV000591309 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Ser316Gly variant was identified at least once in a large cohort of 55630 individuals referred for BRCA1 mutation testing (Judkins 2005). The variant was also identified in dbSNP (ID: rs55874646) “With non-pathogenic allele”, LOVD, the BIC database (6X with unknown clinical importance), and in UMD (5X as a unclassified variant). In UMD the variant was listed twice as co-occurring with a pathogenic mutation in either BRCA1 or BRCA2 (BRCA1 c.3228 3229delAG (p.Gly1077AlafsX8) and BRCA2 c.6209 6212delAAAG (p.Glu2070ValfsX10)), increasing the likelihood that this variant does not have clinical significance. In addition, one in silico study suggests that the variant does not confer a high oncogenic risk (Burk-Herrick 2005). The variant was listed in the NHLBI Exome Sequencing Project with a frequency of 0.0002 in European American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Ser316 residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information 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 predicted benign.

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