rs147852216
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS1
The NM_000179.3(MSH6):c.3788G>A(p.Arg1263His) variant causes a missense change. The variant allele was found at a frequency of 0.000075 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1263C) has been classified as Likely benign.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.3788G>A | p.Arg1263His | missense_variant | 8/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3788G>A | p.Arg1263His | missense_variant | 8/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152120Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000175 AC: 44AN: 251220Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135780
GnomAD4 exome AF: 0.0000711 AC: 104AN: 1461822Hom.: 0 Cov.: 33 AF XY: 0.000102 AC XY: 74AN XY: 727204
GnomAD4 genome AF: 0.000112 AC: 17AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74436
ClinVar
Submissions by phenotype
Lynch syndrome 5 Uncertain:2Benign:1
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 29, 2023 | This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. 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 | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Apr 07, 2023 | A heterozygous missense substitution (p.Arg1263His) lies in exon 8 of the MSH6 gene and alters a conserved residue in the protein. . The in silico prediction of the variant are possibly damaging by LRT, Mutation Taster and SIFT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 04, 2017 | - - |
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 21, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 p.Arg1263His variant was identified in 10 of 1362 chromosomes (frequency: 0.007) from an ancestrally diverse cohort of healthy individuals the literature (Bodian_2014_24728327). The variant was identified in dbSNP (ID: rs147852216) “With Uncertain significance allele”, ClinVar (5x as uncertain significance by GeneDx, Invitae, Color Genomics, Ambry Genetics, ITMI), Clinvitae (3x), and in control databases in 46 of 276952 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24026 chromosomes (freq: 0.00004), Other in 3 of 6460 chromosomes (freq: 0.0005), Latino in 10 of 34386 chromosomes (freq: 0.0003), European Non-Finnish in 7 of 126488 chromosomes (freq: 0.00006), and South Asian in 25 of 30782 chromosomes (freq: 0.0008) while not observed in the Ashkenazi Jewish, East Asian, and European Finnish populations. The variant was not identified in the Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The p.Arg1263 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant His to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2021 | 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: 23621914, 27498913, 24728327, 25186627) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 15, 2023 | This missense variant replaces arginine with histidine at codon 1263 of the MSH6 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 an individual affected with breast cancer (PMID: 25186627), but has also been observed in unaffected individuals (PMID: 4728327, 32980694). This variant has been identified in 47/282612 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 24, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 06, 2021 | 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 specified Uncertain:1Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Endometrial carcinoma;C1833477:Lynch syndrome 5;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at