rs200857129
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_058216.3(RAD51C):c.635G>A(p.Arg212His) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,607,512 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R212C) has been classified as Uncertain significance.
Frequency
Consequence
NM_058216.3 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 | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.635G>A | p.Arg212His | missense_variant | 4/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.635G>A | p.Arg212His | missense_variant | 4/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151938Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251236Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135786
GnomAD4 exome AF: 0.0000213 AC: 31AN: 1455456Hom.: 1 Cov.: 31 AF XY: 0.0000235 AC XY: 17AN XY: 724456
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152056Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate reduced cell viability and double-strand break repair (Kolinjivadi et al., 2022); Observed in individuals with breast cancer or other cancers, but also observed in controls (Pang et al., 2011; Yurgelun et al., 2015; Wong et al., 2016; Pritchard et al., 2018; Wang et al., 2019; Kwong et al., 2020; Akcay et al., 2020; Dorling et al., 2021; Kolinjivadi et al., 2022; Lim et al., 2022; Zheng et al., 2022); This variant is associated with the following publications: (PMID: 29263802, 25980754, 21597919, 25338684, 34426522, 14704354, 34284872, 32566746, 36562461, 33471991, 29641532, 30982232, 32068069, 32658311, 35057767, 35039523) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 21, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 26, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 17, 2022 | This missense variant replaces arginine with histidine at codon 212 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 21597919, 25980754). This variant has been identified in 25/282612 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In a large breast cancer case-control study, this variant was observed in 9/60466 cases and 10/53461 unaffected controls, and did not show significant association with breast cancer (OR=0.796; 95%CI 0.323 to 1.958; p-value=0.652) (Leiden Open Variation Database DB-ID RAD51C_000069, PMID: 33471991). 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2022 | 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 | curation | Sema4, Sema4 | Jan 10, 2022 | - - |
Fanconi anemia complementation group O Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 212 of the RAD51C protein (p.Arg212His). This variant is present in population databases (rs200857129, gnomAD 0.09%). This missense change has been observed in individual(s) with breast cancer and clinical features of Lynch syndrome (PMID: 21597919, 25980754, 29263802, 36562461). ClinVar contains an entry for this variant (Variation ID: 187633). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RAD51C function (PMID: 36562461). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2016 | - - |
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 05, 2023 | 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]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2016 | - - |
Ovarian cancer Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 02, 2022 | Variant summary: RAD51C c.635G>A (p.Arg212His) results in a non-conservative amino acid change located in the ATP-binding 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 9.1e-05 in 252186 control chromosomes (gnomAD and publication). The observed variant frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in RAD51C causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), suggesting that the variant may be benign. c.635G>A has been reported in the literature in individuals affected with cancer including breast cancer, Lynch syndrome and cutaneous melanoma (e.g. Pang_2011, Wong_2015, Yurgelun_2015, Pritchard_2018, Wang_2019, Kwong_2020, Akcay_2021, Krivokuca_2021, Lim_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 18, 2022 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at