rs63749841

chr2-47478498-A-Gchr2-47478498-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BP6_Strong

The NM_000251.3(MSH2):c.2437A>G(p.Met813Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,004 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M813I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:10 B:3
• Conservation: PhyloP100: 8.85

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• BP6: Variant 2-47478498-A-G is Benign according to our data. Variant chr2-47478498-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 90972.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2, Benign=1}. Variant chr2-47478498-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2437A>G	p.Met813Val	missense_variant	14/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2437A>G	p.Met813Val	missense_variant	14/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251338 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000118 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jun 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 13, 2018	Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probabilty is in class 3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 06, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 12, 2015	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is denoted MSH2 c.2437A>G at the cDNA level, p.Met813Val (M813V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been identified in at least one individual with colon cancer whose tumor was shown to be microsatellite stable and exhibit expression of all four mismatch repair proteins on immunohistochemistry (Gille 2002, Wielders 2014). Functional assays conducted in mouse embryonic stem cells demonstrated that this variant displayed protein expression and mismatch repair activity comparable to wild type (Wielders 2014). MSH2 Met813Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Met813Val is located in the ATPase domain (Lutzen 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether MSH2 Met813Val is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 17, 2023	In the published literature, this variant has been reported in individuals with Lynch syndrome (PMIDs: 31386297 (2019), 24501230 (2014), 12373605 (2002)) and healthy, unaffected individuals (PMID: 25637381 (2018)). Experimental studies report the variant does not impact MSH2 function (PMIDs: 33357406 (2021), 24501230 (2014)). The frequency of this variant in the general population, 0.000026 (3/113690 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 16, 2018	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	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2022	This missense variant replaces methionine with valine at codon 813 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). In another functional study, this variant caused no significant difference in microsatellite levels or DNA damage response compared to wild type (PMID: 24501230). This variant has been reported in individuals affected by colorectal cancer but with clinical features not indicative of Lynch syndrome (the tumors exhibited microsatellite stability and the presence of MSH2 protein (PMID: 12373605, 24501230)) and in individuals affected with cancer who did not meet Bethesda Lynch syndrome criteria (PMID: 31386297). This variant has been identified in 3/251338 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 31, 2023

Variant summary: MSH2 c.2437A>G (p.Met813Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251338 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2437A>G has been reported in the literature in suspected or affected Lynch Syndrome individuals/families (example: Gille_2002, Wielders_2014, Kiyozumi_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.1961delA, p.Lys654fsX47; ATM c.2921+1G>T), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated no reduction in protein level and no functional MMR defects for p.M813V and determined it to have similar function to the wild type. Furthermore, tumor analysis showed microsatellite stability and the presence of all four MMR proteins (Gille_2002, Wielders_2014). An additional study shows a neutral effect of the protein (Jia_2021). These data provide further supporting evidence for a benign role of the variant. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 18383312, 12373605, 33357406, 31386297, 24501230). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments; seven submitters classified it as a variant of uncertain significance, two classified it as liekly benign, and one classified it as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 18, 2023

The c.2437A>G (p.Met813Val) variant in MSH2 has been reported in 2 individuals with clinical features of Lynch syndrome (Gille 2002 PMID: 12373605, Wielders 2014 PMID: 24501230). It has also been identified in 0.003% (3/113690) of European (non-Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 90972). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro and in vivo functional studies provide some evidence that this variant does not impact protein function (Wielders 2014 PMID: 24501230), and a tumor derived from a patient with this variant was shown to be microsatellite stable (Gille 2002 PMID: 12373605). In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS3, BS1_Supporting. -

Colorectal cancer, non-polyposis Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.0	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N;N;.;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;D;.;D
Sift4G	Uncertain	0.013	D;D;.;D
Polyphen		0.24	B;.;.;B
Vest4		0.87
MVP		0.98
MPC		0.0070
ClinPred		0.73	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63749841; hg19: chr2-47705637;