rs80357057
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_007294.4(BRCA1):c.1418A>T(p.Asn473Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N473S) has been classified as Benign.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.1418A>T | p.Asn473Ile | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.1418A>T | p.Asn473Ile | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251268Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135794
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461810Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727194
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74346
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 21, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Nov 25, 2004 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 18, 2019 | 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 - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 19, 2019 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 20, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 18, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 16, 2024 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 12, 2023 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 01, 2023 | 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. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at