ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3541G>A (p.Val1181Ile) (rs56336919)

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Total submissions: 9
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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) RCV000112112 SCV001161585 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 = 0.000066
Invitae RCV000203659 SCV000076239 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000590151 SCV000210148 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3541G>A at the cDNA level, p.Val1181Ile (V1181I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant, also known as 3660G>A using alternate nomenclature, was observed in at least one individual with a family history of breast and/or ovarian cancer (Konecny 2011). BRCA1 Val1181Ile was observed at an allele frequency of 0.05% (14/30,778) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Val1181Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509845 SCV000607801 likely benign Hereditary cancer-predisposing syndrome 2019-11-18 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001293422 SCV000699040 benign not specified 2021-02-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3541G>A (p.Val1181Ile) 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. This variant has also been predicted to be neutral by studies based on sequence alignment, chemical difference measurement, and conservation analysis (Abkevich_2004, Pavlicek_2004). A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (CAGI class 1) in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). The variant allele was found at a frequency of 8e-05 in 273756 control chromosomes, predominantly at a frequency of 0.00046 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (8e-05 vs 0.001), allowing no conclusion about variant significance. c.3541G>A, has been reported in the literature in individuals affected with Breast and Ovarian Cancer and in unaffected controls without strong evidence for causality (example, Konecny_2011, Judkins_2005, Yilmaz_2016, Zhang_2015, Momozawa_2018, Fujita_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All but one submitter has rendered a classification as benign (n=1, expert panel)/likely benign (n=4). Based on the lack of any evidence supporting an actionable outcome in a cross-sectional review of literature spanning at-least 16 years of evolution, and the predominant consensus among peers supporting a neutral outcome as outlined above, the variant was classified as benign.
Color Health, Inc RCV000509845 SCV000911018 likely benign Hereditary cancer-predisposing syndrome 2016-05-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590151 SCV001133556 likely benign not provided 2019-04-24 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112112 SCV000144784 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 RCV000590151 SCV001548719 likely benign not provided no assertion criteria provided clinical testing

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