17-35100957-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_002878.4(RAD51D):c.983C>T(p.Thr328Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,611,324 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002878.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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RAD51D | ENST00000345365.11 | c.983C>T | p.Thr328Ile | missense_variant | Exon 10 of 10 | 1 | NM_002878.4 | ENSP00000338790.6 | ||
ENSG00000267618 | ENST00000593039.5 | c.426+244C>T | intron_variant | Intron 5 of 6 | 2 | ENSP00000466834.1 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152196Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251488Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135918
GnomAD4 exome AF: 0.0000446 AC: 65AN: 1459010Hom.: 0 Cov.: 30 AF XY: 0.0000427 AC XY: 31AN XY: 725980
GnomAD4 genome AF: 0.000204 AC: 31AN: 152314Hom.: 1 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74474
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:1Benign:3
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This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Hereditary cancer-predisposing syndrome Benign:3
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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 provided Benign:2
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function This variant is associated with the following publications: (PMID: 25980754) -
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not specified Benign:1
Variant summary: RAD51D c.983C>T (p.Thr328Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 282876 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.983C>T, has been reported in the literature in individuals affected with Lynch syndromeassociated cancer and/or polyps (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a BRCA1 pathogenic variant has been reported (c.3598C>T, p.Gln1200X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions (evaluation after 2014) cite the variant four times as likely benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
RAD51D-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at