ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1418A>T (p.Asn473Ile) (rs80357057)

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Total submissions: 8
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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) RCV000111613 SCV001161486 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 = 0.000525
GeneDx RCV000235125 SCV000210102 uncertain significance not provided 2017-06-08 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1418A>T at the cDNA level, p.Asn473Ile (N473I) at the protein level, and results in the change of an Asparagine to an Isoleucine (AAC>ATC). Using alternate nomenclature, this variant would be defined as BRCA1 1537A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Asn473Ile was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Asn473Ile occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interaction with multiple other proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Asn473Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000215347 SCV000274394 likely benign Hereditary cancer-predisposing syndrome 2019-08-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Color Health, Inc RCV000215347 SCV000682960 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-22 criteria provided, single submitter clinical testing
Counsyl RCV000111613 SCV000785119 uncertain significance Breast-ovarian cancer, familial 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 2021-01-02 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. A recent 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). The variant allele was found at a frequency of 1.6e-05 in 251268 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. 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). This report(s) 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. 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. The expert panel (ENIGMA) and one clinical diagnostic laboratory 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.
Invitae RCV001340961 SCV001534796 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 473 of the BRCA1 protein (p.Asn473Ile). The asparagine residue is weakly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is present in population databases (rs80357057, ExAC 0.01%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333) and the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 54249). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 31131967). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111613 SCV000144089 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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