rs80357013
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_007294.4(BRCA1):c.4261C>T(p.His1421Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1421L) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.4261C>T | p.His1421Tyr | missense_variant | 12/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.4261C>T | p.His1421Tyr | missense_variant | 12/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251434Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135890
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461832Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727222
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74346
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 09, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Feb 03, 2010 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Feb 15, 1997 | - - |
not provided Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2021 | This variant is associated with the following publications: (PMID: 26689913, 16267036, 21447777, 22682623, 17925560, 12080089, 9333265, 24845084, 18259752, 15689452, 28781887, 30400234, 30765603, 31131967, 15343273, 22737296, 19369211) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 30, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 04, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 23, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 14, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 24, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 09, 2023 | Variant summary: BRCA1 c.4261C>T (p.His1421Tyr) 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. The variant allele was found at a frequency of 1.2e-05 in 252434 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4261C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer or at high risk, without strong evidence for causality (examples, Shattuck-Eidens_1997, Dutil_2012, Vogel_2007, Judkins_2005, Diaz-Zabala_2018, Grant_2015, Ren_2021), it has also been reported in a control cohort (example, Dorling_2021). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (Dutil_2012, pathogenic variant not provided) for this variant, supporting evidence for a benign role. Several functional experiments suggest that this variant has transcriptional and HDR activity similar to that of wild-type (Carvalho_2010, Hu_2002, Lu_2015, Woods_2016). The following publications have been ascertained in the context of this evaluation (PMID: 18992264, 30400234, 22682623, 30765603, 25479140, 12080089, 21447777, 16267036, 18259752, 26689913, 15385441, 15689452, 34196900, 9333265, 23704879, 17925560, 28781887). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely benign n=5, VUS n=5). Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at