rs80358747
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5BP4_ModerateBP6
The NM_000059.4(BRCA2):c.521G>A(p.Arg174His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,609,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. R174C) has been classified as Pathogenic.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.521G>A | p.Arg174His | missense_variant | 7/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.521G>A | p.Arg174His | missense_variant | 7/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.152G>A | p.Arg51His | missense_variant | 7/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.521G>A | non_coding_transcript_exon_variant | 6/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251348Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135834
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1457446Hom.: 0 Cov.: 30 AF XY: 0.00000965 AC XY: 7AN XY: 725344
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74326
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 05, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 12, 2023 | 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. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:1
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 23, 2003 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 06, 2024 | The BRCA2 c.521G>A (p.Arg174His) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 37277882 (2023), 18284688 (2008), 15955690 (2005)), and in reportedly healthy individuals (PMIDs: 32467295 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). One study reported this variant caused partial splicing defect (PMID: 23983145 (2013)), but two other studies reported normal splicing (PMIDs: 22505045 (2012), 31143303 (2019)). The frequency of this variant in the general population, 0.000018 (5/282754 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 09, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at