chr2-47803546-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6
The NM_000179.3(MSH6):c.3299C>T(p.Thr1100Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,613,980 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. T1100R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000179.3 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 |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.3299C>T | p.Thr1100Met | missense_variant | 5/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.3299C>T | p.Thr1100Met | missense_variant | 5/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251432Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135886
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461886Hom.: 0 Cov.: 33 AF XY: 0.0000316 AC XY: 23AN XY: 727242
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74302
ClinVar
Submissions by phenotype
not specified Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 03, 2024 | Variant summary: MSH6 c.3299C>T (p.Thr1100Met) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) 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 4e-05 in 251432 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (4e-05 vs 0.00014), allowing no conclusion about variant significance. c.3299C>T has been reported in the literature in individuals affected with or suspected to have Hereditary Nonpolyposis Colorectal Cancer, or colorectal cancer or breast cancer (Example: Ackay_2021, Schuber_2020, Berends_2002, deVoer_2016, Kwong_2020). The variant was also reported to cosegregate with heterozygous pathogenic MUTYH p.Tyr179Cys in multiple colorectal cancer-affected members of a suspected Lynch syndrome family (Schuber_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one publication reports experimental evidence evaluating an impact on protein function (Schuber_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 11709755, 25801821, 31422818, 32068069, 32615015, 23621914, 25980754, 26901136, 35449176). ClinVar contains an entry for this variant (Variation ID: 89369). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 25, 2017 | The p.Thr1100Met variant in MSH6 has been reported in 2 individuals with suspect ed colorectal cancer or Lynch syndrome (Berends 2002, Yurgelun 2015). This varia nt has also been identified in 2/16512 of South Asian chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs63750442). Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. In addition, the p.Thr1100Met va riant has been classified as a variant of uncertain significance on Sept 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108047.2). In summ ary, the clinical significance of the p.Thr1100Met variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 23, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2023 | 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 | Jun 04, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 05, 2023 | This missense variant replaces threonine with methionine at codon 1100 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). A functional study has reported that this variant does not impact in vitro DNA mismatch repair activity (PMID: 32615015). This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 11709755, 25980754, 26901136, 30267214) and skin melanoma and thyroid cancer (PMID: 2968408). This variant also has been reported to cosegregate with heterozygous pathogenic MUTYH p.Tyr179Cys in three colorectal cancer-affected members of a suspected Lynch syndrome family (PMID: 32615015). This variant has been identified in 12/282832 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy controls (PMID: 32980694). 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. - |
Lynch syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Mar 11, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces threonine with methionine at codon 1100 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). A functional study has reported that this variant does not impact in vitro DNA mismatch repair activity (PMID: 32615015). This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 11709755, 25980754, 26901136, 30267214) and skin melanoma and thyroid cancer (PMID: 2968408). This variant also has been reported to cosegregate with heterozygous pathogenic MUTYH p.Tyr179Cys in three colorectal cancer-affected members of a suspected Lynch syndrome family (PMID: 32615015). This variant has been identified in 12/282832 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy controls (PMID: 32980694). 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 03, 2023 | In the published literature, the variant has been reported in individuals with colorectal cancer (PMIDs: 11709755 (2002), 26901136 (2016), 32658311 (2021), 30267214 (2018)), breast cancer (PMID: 32068069 (2020)) and suspected lynch syndrome (25980754 (2015)). In one family, this variant was found to co-occur with a pathogenic MUTYH variant in 3 individuals with colorectal cancer (PMID: 32615015 (2020)). One functional study demonstrated this variant has a mismatch repair efficiency similar to wildtype MSH6 in vitro (PMID: 32615015 (2020)). The frequency of this variant in the general population, 0.000031 (4/129154 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2023 | Observed in patients with melanoma, thyroid, colorectal, or other Lynch syndrome-associated cancers, co-segregating with CRC in one family together with a MUTYH pathogenic variant (Berends et al., 2002; Yurgelun et al., 2015; de Voer et al., 2016; Rosenthal et al., 2018; Yehia et al., 2018; Schubert et al., 2020); Published functional studies demonstrate no damaging effect: mismatch repair activity similar to wild-type (Schubert et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25801821, 32615015, 32980694, 25980754, 23621914, 24362816, 26269718, 26901136, 11709755, 35422474, 32658311, 33471991, 29684080, 17531815, 21120944, 30267214, 31422818, 32068069) - |
MSH6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 26, 2024 | The MSH6 c.3299C>T variant is predicted to result in the amino acid substitution p.Thr1100Met. This variant has been reported in individuals with Lynch syndrome-associated cancers such as colorectal cancers and in controls (Examples: Table 1. Berends et al 2002. PubMed ID: 11709755; Supplemental Table 2. Yurgelun et al 2015. PubMed ID: 25980754; Supplemental Table 2. Rosenthal EA et al 2018. PubMed ID: 30267214; Table S2. Okawa et al 2022. PubMed ID: 36243179). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89369/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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 | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 p.Thr1100Met variant was identified in 3 of 3262 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Berends 2002, de Voer 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs63750442) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Color Genomics, and 5 clinical laboratories), Clinvitae, Cosmic, MutDB, UMD-LSDB (1X classified as uncertain significance), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database (as unclassified variant) databases. The variant was not identified in GeneInsight-COGR, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 277180 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: African in 2 of 24038 chromosomes (freq: 0.0001), “Other” in 1 of 6464 chromosomes (freq: 0.0002), European in 5 of 126684 chromosomes (freq: 0.00004), East Asian in 1 of 18868 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the Latino, Ashkenazi Jewish, or Finnish populations. The p.Thr1100 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact 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. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 04, 2024 | - - |
Lynch syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 23, 2024 | 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: 27363726]. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at