2-47403192-A-G
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PS1_Moderate
The NM_000251.3(MSH2):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000832 in 1,441,876 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 Uncertain significance (★★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000083 ( 0 hom. )
Consequence
MSH2
NM_000251.3 start_lost
NM_000251.3 start_lost
Scores
8
6
2
Clinical Significance
Conservation
PhyloP100: 7.84
Genes affected
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000251.3 (MSH2) was described as [Pathogenic] in Lovd
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.0000140 AC: 3AN: 214858Hom.: 0 AF XY: 0.0000257 AC XY: 3AN XY: 116898
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GnomAD4 exome AF: 0.00000832 AC: 12AN: 1441876Hom.: 0 Cov.: 31 AF XY: 0.00000839 AC XY: 6AN XY: 715500
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33
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2015 | The c.1A>G variant in the MSH2 gene results in the loss of the initiator Methionine codon, and the resultant protein would be described as ?p.Met1?? to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. This variant was reported in two siblings who were compound heterozygotes for MSH2 c.1A>G and a known pathogenic MSH2 deletion in the absence of constitutional mismatch repair-deficiency (CMMR-D) syndrome, but who did display a phenotype more severe than classical Lynch syndrome, leading the authors to suggest that a variant in this start codon may be associated with reduced penetrance (Kets 2009). Additionally, the unaffected mother was found to only harbor the MSH2 c.1A>G variant, which in combination with the lack of Lynch syndrome-associated cancers in her family, further supports a less severe phenotype than classic Lynch syndrome. Corresponding tumor studies from the siblings showed weak MSH2 staining and microsatellite instability, suggesting that this variant confers reduced, but not complete, loss of protein activity. Another initiation codon variant, MSH2 c.1A>C, has also been suggested to be associated with an attenuated Lynch syndrome phenotype. This variant demonstrated impaired, but not complete loss of protein activity, and has been shown to produce multiple protein products, including both full-length and truncated MSH2 protein (Barnetson 2006, Barnetson 2008, Cyr 2012). Thus, the effects of these two start codon missense variants appear to be similar. There is some published evidence that this variant increases the risk of Lynch-related cancers (colon, endometrial, etc.) in the heterozygous state. However, based on internal data acquired from multiple observations of this variant and MSH2 c.1A>C in individuals without histories suggestive of Lynch syndrome, the cancer risks associated with this variant may be lower than what is expected for typical Lynch syndrome. Based on currently available data the cancer risks associated with MSH2 c.1A>G are not well understood, thus we consider it to be a variant of uncertain significance. - |
Lynch syndrome 1 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Pathway Genomics | Oct 30, 2014 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 13, 2023 | The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the MSH2 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however there is an alternate in-frame methionine 25 amino acids from the initiation site and the significance of the N-terminus for this protein is not well established. This alteration has been reported in trans with a pathogenic MSH2 gross deletion in two siblings whose phenotypes were in the monoallelic HNPCC spectrum; however, microsatellite instability (MSI) and immunohistochemical (IHC) data were conflicting and the number of adenomas in one of the siblings was higher than expected (Kets CM, Eur. J. Hum. Genet. 2009 Feb; 17(2):159-64). This alteration has also been reported in one of 43 pancreatic cancer patients who also carried germline CDKN2A mutations (Yang XR et al. Hum. Genet., 2016 Nov;135:1241-1249). This alteration was also detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). Alterations at the initiation codon of MSH2 have been identified in several cancer cohorts including ovarian cancer, early-onset colorectal cancer (diagnosed under age 30) and known or suspected Lynch syndrome cases; however, tumors do not consistently demonstrate a pattern of MSI and mismatch repair protein-deficient IHC staining (Farrington SM et al. Am. J. Hum. Genet. 1998 Sep 63(3):749-59; Otway R et al. Hum. Mutat. 2000;16(1):61-7; Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354(26):2751-63; Barnetson RA et al. Hum. Mutat. 2008 Mar;29(3):367-74; Pal T et al. Br. J. Cancer. 2012 Nov;107(10):1783-90; Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). Further, transfection of a similar alteration impacting the initiation codon of MSH2, c.1A>C, cDNA into an MSH2-null, human endometrial cancer cell line showed slight, but statistically significant decrease in repair of an exogenous mismatched protein. This attenuated effect may be due to partial function of the truncated protein and/or expression of the full-length protein resulting from weak translation at the altered, non-AUG start codon, which was detected concomitantly with the truncated protein in this study (Cyr JL et al. Mol. Carcinog. 2012 Aug;51(8):647-58). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 25, 2023 | This variant alters the translation initiation codon methionine of the MSH2 protein. To our knowledge, functional studies have not been reported for this variant, and it is unknown whether this variant impacts the full length protein expression or results in the use of alternate downstream methionine for translation initiation (PMID: 21837758). This variant has been reported in trans with a pathogenic MSH2 variant in two siblings who did not present with constitutional mismatch repair deficiency syndrome, but were affected with multiple, early-onset Lynch syndrome-related cancers (PMID: 18781192). Their phenotypes were more suggestive of a monoallelic mutation, and tumors showed microsatellite instability in the presence of MLH1, PMS2, MSH2 and MSH6 proteins (PMID: 18781192). This variant was found in the probands' unaffected mother in her 80s, who lacked family history of Lynch syndrome-associated cancers. This variant has been reported in an individual affected with pancreatic cancer, who also carried a pathogenic variant in the CDKN2A gene (PMID: 27449771). This variant has been identified in 3/214858 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. - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Lynch syndrome Uncertain:1
| Uncertain significance, reviewed by expert panel | curation | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Jun 21, 2019 | Insufficient evidence - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 06, 2023 | This sequence change affects the initiator methionine of the MSH2 mRNA. The next in-frame methionine is located at codon 26. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 26 has the potential to rescue this variant. This variant is present in population databases (rs267607911, gnomAD 0.006%). Disruption of the initiator codon has been observed in individual(s) with MSH2-related cancers (PMID: 9718327, 10874307, 18033691, 18781192, 21837758, 23047549, 25639900, 27449771, 28944238). Disruption of the initiator codon has been observed on the opposite chromosome (in trans) from a pathogenic variant in MSH2 in an individual who was not affected with recessive MSH2-related conditions (PMID: 18781192, 25639900). This suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 90833). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
PROVEAN
Benign
N;.;N
REVEL
Pathogenic
Sift
Pathogenic
D;.;D
Sift4G
Pathogenic
D;.;D
Polyphen
P;.;P
Vest4
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at