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

gnomAD frequency: 0.00001  dbSNP: rs56336919

Total submissions: 15

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, susceptibility to, 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203659	SCV000076239	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-29	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 Diagnostics, LLC DBA Color Health	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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590151	SCV002048567	likely benign	not provided	2020-12-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001293422	SCV002066796	uncertain significance	not specified	2021-01-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.3541G>A, in exon 10 that results in an amino acid change, p.Val1181Ile. This sequence change has been described in the gnomAD database with a frequency of 0.046% in the South Asian sub-population (dbSNP rs56336919). The p.Val1181Ile change has been reported in one case-control study; however, its presence in cases versus controls was not specified (PMID: 30287823). Additionally, a different amino acid change at the same location, p.Val1181Ala, has been reported in association with breast and/or ovarian cancer (PMID: 30702160). The p.Val1181Ile change affects a moderately conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Val1181Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val1181Ile change remains unknown at this time.
Sema4, Sema4	RCV000509845	SCV002538214	likely benign	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001293422	SCV002550997	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112112	SCV004817791	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-20	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112112	SCV000144784	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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
PreventionGenetics, part of Exact Sciences	RCV004554661	SCV004727360	likely benign	BRCA1-related disorder	2023-04-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).