ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4213A>G (p.Ile1405Val) (rs80357353)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001078939 SCV000076503 likely benign Hereditary breast and ovarian cancer syndrome 2020-07-27 criteria provided, single submitter clinical testing
GeneDx RCV000444773 SCV000516168 likely benign not specified 2017-03-09 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 RCV000565302 SCV000668387 likely benign Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Subpopulation frequency in support of benign classification
Color Health, Inc RCV000565302 SCV000683163 likely benign Hereditary cancer-predisposing syndrome 2016-01-04 criteria provided, single submitter clinical testing
Counsyl RCV000031156 SCV000785577 uncertain significance Breast-ovarian cancer, familial 1 2017-09-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679696 SCV000806947 likely benign not provided 2017-10-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000444773 SCV000916735 likely benign not specified 2021-01-15 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4213A>G (p.Ile1405Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 348962 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.00039 within the South Asian 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 (4.3e-05 vs 0.001), allowing no conclusion about variant significance. c.4213A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Easton_2007, Shimelis_2017, Santonocito_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function by measuring transcriptional activity in a yeast-based system, and when combined with computational algorithms predicting variant effects, classified the variant as "likely not pathogenic" (e.g. Woods_2016, Fernandes_2019). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=5) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Sharing Clinical Reports Project (SCRP) RCV000031156 SCV000053756 benign Breast-ovarian cancer, familial 1 2011-04-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031156 SCV000145031 uncertain significance Breast-ovarian cancer, familial 1 1999-04-05 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000031156 SCV001550385 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Ile1405Val variant was identified in the literature; however, the frequency of this variant in an affected population was not provided (Abkevich 2004, Easton 2007). The variant was also identified in dbSNP (ID: rs80357353) as "With other allele", ClinVar (classified as benign by SCRP; as likely benign by Invitae, Ambry Genetics, GeneDx, and two other submitters; and as uncertain significance by Counsyl and BIC), COGR, MutDB , LOVD 3.0 (2x ), UMD-LSDB (2x unclassified variant), and BIC Database (2x with unknown significance). The variant was not identified in Cosmic, ARUP Laboratories, or Zhejiang University Database. The variant was identified in control databases in 15 of 246146 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111622 chromosomes (freq: 0.00003) and South Asian in 12 of 30782 chromosomes (freq: 0.0004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ile1405 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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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