2-47476424-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):c.2063T>G(p.Met688Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M688I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 7.67

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 12 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47476423-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1324737.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 2-47476424-T-G is Pathogenic according to our data. Variant chr2-47476424-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 90874.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476424-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2063T>G	p.Met688Arg	missense_variant	13/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2063T>G	p.Met688Arg	missense_variant	13/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The p.Met688Arg variant has been reported in the literature in 75/1312 proband chromosomes of individuals meeting the Amsterdam and Bethesda criteria for HNPCC (Ali 2012, Lin 1999, Martin-Lopez 2012, Medina-Arana 2006, Medina-Arana 2011, Pastrello 2011); it was not identified in any of the 320 control chromosomes tested. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs63749993), but no frequency information was provided, and so the prevalence of this variant in the population is not known. The p.Met688 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Met688Arg variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Functional assays have found the p.Met688Arg variant to defective in ATP processing functions, and that the hMSH2(M688R)–hMSH6 protein can functionally inhibit the wildtype hMSH2–hMSH6 during the mismatch excision process (Martin-Lopez 2012). In addition, HNPCC-associated tumors from carriers were MSI-H, MSH2 deficient by immunohistochemistry and exhibited loss of heterozygosity for the normal allele (Martin-Lopez 2012, Medina-Arana 2006, Medina-Arana 2011, Pastrello 2011), increasing the likelihood that this variant is pathogenic. In summary, based on the above information, this variant is classified as pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability >0.99 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 12, 2019

Not found in the total gnomAD dataset. Segregation with disease in affected individuals from a single family. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 23, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MSH2 function (PMID: 22739024). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 90874). This missense change has been observed in individuals with Lynch syndrome (PMID: 10080150, 15075785, 20010080, 21225464, 21239990, 22739024). It is commonly reported in individuals of Canary Islander ancestry (PMID: 15075785, 20010080, 22739024). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 688 of the MSH2 protein (p.Met688Arg). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2023

The p.M688R pathogenic mutation (also known as c.2063T>G), located in coding exon 13 of the MSH2 gene, results from a T to G substitution at nucleotide position 2063. The methionine at codon 688 is replaced by arginine, an amino acid with very few similar properties. This pathogenic mutation has been reported in multiple families with HNPCC/Lynch syndrome (Lin X et al. Dig. Dis. Sci. 1999 Mar; 44(3):553-9; Pastrello C et al. Genet. Med. 2011 Feb; 13(2):115-24). In one study, this pathogenic mutation was reported in five unrelated families from Spain that not only had tumors associated with Lynch syndrome, but also had numerous incidences of CNS tumors associated with Turcot syndrome or CMMR-D. In vitro functional assays indicated that the hMSH2(M688R)-hMSH6 heterodimer lacked normal ATP functions and inhibited MMR activity of the wild-type heterodimer (Martín-López JV et al. Carcinogenesis 2012 Sep; 33(9):1647-54). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Lynch syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	30
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.6	D;D;.;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.95		Gain of catalytic residue at M688 (P = 0.0265);.;Gain of catalytic residue at M688 (P = 0.0265);Gain of catalytic residue at M688 (P = 0.0265);
MVP		0.97
MPC		0.030
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs63749993; hg19: chr2-47703563;