rs144848
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000059.4(BRCA2):c.1114A>C(p.Asn372His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,613,510 control chromosomes in the GnomAD database, including 63,594 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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BRCA2 | ENST00000380152.8 | c.1114A>C | p.Asn372His | missense_variant | Exon 10 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.745A>C | p.Asn249His | missense_variant | Exon 10 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.1114A>C | non_coding_transcript_exon_variant | Exon 9 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.238 AC: 36156AN: 151966Hom.: 4768 Cov.: 32
GnomAD3 exomes AF: 0.280 AC: 69869AN: 249852Hom.: 10214 AF XY: 0.285 AC XY: 38560AN XY: 135500
GnomAD4 exome AF: 0.281 AC: 409992AN: 1461426Hom.: 58821 Cov.: 37 AF XY: 0.283 AC XY: 205796AN XY: 726994
GnomAD4 genome AF: 0.238 AC: 36183AN: 152084Hom.: 4773 Cov.: 32 AF XY: 0.239 AC XY: 17733AN XY: 74322
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:11
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.2552 (Asian), 0.09756 (African), 0.2876 (European), derived from 1000 genomes (2012-04-30). -
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High frequency in a 1kG or ESP population: 28.6 %. -
not specified Benign:8Other:1
p.Asn372His in exon 10 of BRCA2: This variant is not expected to have clinical s ignificance because it has been identified in 35.58% (5867/16490) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs144848). -
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not provided Benign:5
This variant is associated with the following publications: (PMID: 32846166, 25348552, 21476145, 24289560, 32356124, 31477031, 29988080, 21990134, 24728327, 26306726, 27153395, 11062481, 19253839, 18288416, 22044372, 24323938, 23249957, 14555511, 15695382, 21702907, 17767707, 21952622, 20352487, 20135345, 22703879) -
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Hereditary breast ovarian cancer syndrome Benign:4
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Hereditary cancer-predisposing syndrome Benign:3
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This alteration is classified as 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. -
Familial cancer of breast Benign:2
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Breast ductal adenocarcinoma Uncertain:1
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Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Benign:1
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BRCA2-related cancer predisposition Benign:1
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Fanconi anemia complementation group D1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Breast carcinoma Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at