chr5-132642194-T-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_005732.4(RAD50):c.3769T>G(p.Ser1257Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S1257L) has been classified as Uncertain significance.
Frequency
Consequence
NM_005732.4 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 |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.3769T>G | p.Ser1257Ala | missense_variant | 25/25 | ENST00000378823.8 | |
TH2LCRR | NR_132125.1 | n.189+4A>C | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | ||||
TH2LCRR | NR_132126.1 | n.175-3929A>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3769T>G | p.Ser1257Ala | missense_variant | 25/25 | 1 | NM_005732.4 | P1 | |
TH2LCRR | ENST00000435042.1 | n.183A>C | non_coding_transcript_exon_variant | 2/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152236Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251300Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135822
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461750Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727180
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74372
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2022 | The p.S1257A variant (also known as c.3769T>G), located in coding exon 25 of the RAD50 gene, results from a T to G substitution at nucleotide position 3769. The serine at codon 1257 is replaced by alanine, an amino acid with similar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol. 2020 Jan;4:32-43). This amino acid position is highly 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 05, 2018 | Variant summary: RAD50 c.3769T>G (p.Ser1257Ala) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246058 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3769T>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 01, 2023 | In the published literature, this variant has been reported in a cohort of African American men undergoing multigene panel testing (PMID: 32832836 (2020)). The frequency of this variant in the general population, 0.000014 (4/282710 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. - |
Nijmegen breakage syndrome-like disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 04, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at