Submissions for variant NM_007294.4(BRCA1):c.1418A>T (p.Asn473Ile)

dbSNP: rs80357057

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111613	SCV001161486	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 = 0.000525
GeneDx	RCV000235125	SCV000210102	uncertain significance	not provided	2024-02-16	criteria provided, single submitter	clinical testing	Identified in an individual meeting referral criteria for hereditary cancer genetic testing (PMID: 34413315); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 1537A>T; This variant is associated with the following publications: (PMID: 31294896, 31422574, 31131967, 31112341, 29884841, 32377563, 34413315, 15343273)
Ambry Genetics	RCV000215347	SCV000274394	likely benign	Hereditary cancer-predisposing syndrome	2019-08-19	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.
Color Diagnostics, LLC DBA Color Health	RCV000215347	SCV000682960	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 473 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals with personal or family history of breast, ovarian and other cancer (PMID: 31422574, 34413315). A multifactorial analysis has reported likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant and family history of 0.34, 1.1391 and 0.0665, respectively (PMID: 31131967). This variant has been identified in 6/282674 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl	RCV000111613	SCV000785119	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-02-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779907	SCV000916817	uncertain significance	not specified	2023-06-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1418A>T (p.Asn473Ile) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251268 control chromosomes in GnomAD. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. A report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign (IARC 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). c.1418A>T has been reported in the literature in at-least one individual from a study reporting the prevalence of secondary findings in 19 genes to include BRCA1 and 2 among a retrospective "non-cancer" related cohort (Kraemer_2019) and in one individual from a genetic epidemiology study of BRCA across Latin America (Herzog_2021). These reports does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Another study lists this variant as an IARC class 1 (Benign) variant based on a multifactorial likelihood analysis (Parsons_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31294896, 34413315, 31422574, 31112341, 31131967). Six clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. The expert panel (ENIGMA) and two clinical diagnostic laboratories reported a benign and likely benign outcome, respectively. All other submitters report a VUS outcome. Based on the evidence outlined above, due to absence of concrete functional and clinical evidence, the variant was classified as VUS-possibly benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001340961	SCV001534796	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000215347	SCV002538024	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235125	SCV004222565	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0001201 (3/24972 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a non-cancer cohort with limited information (PMID: 31422574 (2019)). Additionally, a multifactorial likelihood analysis determined this variant to have a low probability of being pathogenic (PMID: 31131967 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000111613	SCV004818331	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 473 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals with personal or family history of breast, ovarian and other cancer (PMID: 31422574, 34413315). A multifactorial analysis has reported likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant and family history of 0.34, 1.1391 and 0.0665, respectively (PMID: 31131967). This variant has been identified in 6/282674 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111613	SCV000144089	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing