ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1974G>C (p.Met658Ile) (rs55678461)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000590433 SCV000075682 benign not provided 2019-02-25 criteria provided, single submitter clinical testing
GeneDx RCV000047669 SCV000167247 benign not specified 2014-02-28 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.
Ambry Genetics RCV000130602 SCV000185477 likely benign Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,In silico models in agreement (benign)
Counsyl RCV000111744 SCV000488131 uncertain significance Breast-ovarian cancer, familial 1 2016-01-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000047669 SCV000591360 benign not specified 2016-03-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000047669 SCV000593683 uncertain significance not specified 2016-09-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590433 SCV000698903 likely benign not provided 2017-03-02 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1974G>C (p.Met658Ile) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 4/4 in silico tools (SNPs&GO not captured due to low reliability index). It is located outside of any known functional domain or repeat in BRCA1 protein (InterPro), however no functional studies confirming the impact of this variant on protein function have been published at the time of evaluation. This variant was found in 7/121328 control chromosomes, exclusively observed in the European (Non-Finnish) subpopulation at a frequency of 0.000105 (7/66700). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). gnomAD database (early beta version, therefore not used for evaluation purposes) list the variant the in Ashkenazi Jewish subpopulation identified in case-control IBD study participants with an allele frequency of 0.001479 (15/10144 chromosomes) which slightly exceeds the estimated maximal expected allele frequency of a pathogenic BRCA1 variant, suggesting it is likely a benign polymorphism found in Ashkenazi Jewish. Of note, 15 out of 27 affected individuals reported in BIC are of Ashkenazi ethnicity. This data also supports that it may be a polymorphism found in patients and controls of Ashkenazi ethnicity and one individual also carried a known pathogenic variant BRCA1 c.68_69delAG, strongly suggesting a benign outcome for c.1974G>C. c.68_69delAG a known founder mutation in AJ population is reported 28/66414 in European subpopulation of ExAC and 38/ 10150 in IBD cohort in gnomAD, further confirming neutrality of c.1974G>C. The variant of interest, c.1974G>C have been reported in literature in multiple HBOC patients/families without strong support for or against pathogenicity (Judkins_2005, Lu_2012, Li_2012). Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as VUS/Likely Benign/Benign. Therefore, taking all available evidence into consideration, the variant of interest is classified as Likely benign until additional information becomes available.
Color RCV000130602 SCV000902675 likely benign Hereditary cancer-predisposing syndrome 2015-06-08 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111744 SCV000144266 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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