rs61756468
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2
The NM_000251.3(MSH2):c.1886A>G(p.Gln629Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,614,156 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q629E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.1886A>G | p.Gln629Arg | missense_variant | 12/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.1886A>G | p.Gln629Arg | missense_variant | 12/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000545 AC: 83AN: 152166Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00120 AC: 303AN: 251464Hom.: 0 AF XY: 0.00112 AC XY: 152AN XY: 135902
GnomAD4 exome AF: 0.000383 AC: 560AN: 1461872Hom.: 4 Cov.: 33 AF XY: 0.000364 AC XY: 265AN XY: 727240
GnomAD4 genome ? AF: 0.000545 AC: 83AN: 152284Hom.: 1 Cov.: 32 AF XY: 0.000618 AC XY: 46AN XY: 74460
ClinVar
Submissions by phenotype
not specified Benign:6Other:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 03, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 17, 2021 | - - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 02, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Lynch syndrome 1 Uncertain:1Benign:2
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Jul 04, 2017 | - - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 02, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2014 | This alteration is classified as 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 24, 2020 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 06, 2016 | Variant summary: The MSH2 c.1886A>G (p.Gln629Arg) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 159/123118 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0174486 (151/8654). This frequency is about 31 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has also been reported in colorectal patients or HNPCC-related cancer without strong evidence for pathogenicity. In a family, while affected proband carried the variant, another affected cousin did not carry the variant, possibly suggesting that it did not co-segregate with disease in the family (Woo_2014). Multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as Benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 29, 2018 | This variant is associated with the following publications: (PMID: 24933000, 22995991, 22283331, 22949387, 29506494, 27487738, 15365995, 21155023, 22290698, 20965939, 23760103, 24728327, 12132870, 26332594, 25985138, 24078570, 29642919, 15996210, 16929514, 18257912, 18383312, 18636359, 18726168, 24396821, 28580595) - |
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 07, 2022 | - - |
Carcinoma of colon Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH2 p.Gln629Arg variant was identified in 8 of 882 proband chromosomes (frequency: 0.009) from individuals or families with colon cancer, gastric cancer, and hepatocellular carcinoma (Jin 2008, Lee 2005, Lim 2010, Shin 2004, Wang 2006, Yano 2007, Yap 2009, Zhang 2006). Yuan (2004) also found the variant in 7 of 200 chromosomes in unaffected individuals (freq 0.035), and therefore classified the variant as a polymorphism. The variant was also identified in dbSNP (ID: rs61756468) as “With Uncertain significance allele”, ClinVar (as benign, reviewed by an expert panel), Clinvitae (as benign), Cosmic, Insight Colon Cancer Gene Variant Database (reported 19x as benign), Zhejiang Colon Cancer Database (reported 6x), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was not identified in MutDB, UMD-LSDB, MMR Gene Unclassified Variants Database. The variant was identified in control databases in 317 of 277184 chromosomes at a frequency of 0.0011 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 304 (1 homozygous) of 18870 chromosomes (freq: 0.01611), Other in 2 of 6464 chromosomes (freq: 0.000309), European (Non-Finnish) in 1 of 126690 chromosomes (freq: 0.000008), European (Finnish) in 3 of 25786 chromosomes (freq: 0.000116), and South Asian in 7 of 30782 chromosomes (freq: 0.000227), while the variant was not observed in the African, Latino, or Ashkenazi Jewish populations. The p.Gln629 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
Lynch syndrome Benign:1
Benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability <0.001 - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 30, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at