rs786201848
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_058216.3(RAD51C):c.621T>A(p.His207Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,455,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. H207R) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.621T>A | p.His207Gln | missense_variant | 4/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.621T>A | p.His207Gln | missense_variant | 4/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251246Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135786
GnomAD4 exome AF: 0.00000756 AC: 11AN: 1455554Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 724512
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 06, 2023 | This missense variant replaces histidine with glutamine at codon 207 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 individuals affected with breast or ovarian cancer (PMID: 29522266) and in a breast cancer case-control meta-analysis in 3/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000154). This variant has been identified in 3/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2023 | The p.H207Q variant (also known as c.621T>A), located in coding exon 4 of the RAD51C gene, results from a T to A substitution at nucleotide position 621. The histidine at codon 207 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in 3/60466 breast cancer cases and in 1/53461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer. (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration demonstrated retained homology-directed repair (HDR) activity in one functional study (Hu C et al. Cancer Res, 2023 May;:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 10, 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 | Baylor Genetics | Mar 17, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 27, 2019 | - - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the RAD51C protein (p.His207Gln). This variant is present in population databases (rs786201848, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29522266). ClinVar contains an entry for this variant (Variation ID: 184991). 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%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at