rs63749879

Positions:

• chr2-47416377-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000251.3(MSH2):​c.1024G>A​(p.Val342Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.13

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 11) in uniprot entity MSH2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1024G>A	p.Val342Ile	missense_variant	6/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1024G>A	p.Val342Ile	missense_variant	6/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2019	Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30998989, 26951660, 24278394, 26333163, 22949387, 18383312, 22290698, 10446963, 14504054, 17192056, 15862756) -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 06, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 19, 2018	The p.V342I variant (also known as c.1024G>A), located in coding exon 6 of the MSH2 gene, results from a G to A substitution at nucleotide position 1024. The valine at codon 342 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was first reported in an Italian patient with an early-onset, MSI-H colon cancer which showed loss of MSH2 protein expression; however, deletion/duplication analysis and analysis of the non-coding regions were not performed (Curia MC et al. Cancer Res. 1999 Aug 1;59(15):3570-5). This variant has also been reported in three Italian families with at least 3 cases of colorectal cancer; in one family, this variant was detected in conjunction with a pathogenic MSH2 mutation (Colombino M et al. Ann Oncol. 2003 Oct;14(10):1530-6; Colombino M et al. Eur. J. Cancer, 2005 May;41:1058-64). In a functional screen utilizing oligo targeting mutagenesis in mouse embryonic stem cells, this alteration rendered cells somewhat resistant to a DNA-damaging agent, showed reduced protein expression levels compared to wild type MSH2, and demonstrated microsatellite instability in an assay that measured DNA polymerase slippage errors at repetitive sequences (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113(15):4128-33). This alteration has been classified as a variant of unknown significance by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be borderline deleterious and neutral by MAPP-MMR and PON-MMR in silico analyses, respectively (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60; Ali H et al. Hum Mutat. 2012 Apr;33(4):642-50). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 29, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 342 of the MSH2 protein (p.Val342Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer, Lynch syndrome or breast cancer (PMID: 14504054, 15862756, 17192056, 24278394; Invitae). ClinVar contains an entry for this variant (Variation ID: 90508). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH2 function (PMID: 26951660, 30998989, 33357406). 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. -

Endometrial carcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH2 p.Val342Ile variant was identified in 3 of 396 proband chromosomes (frequency: 0.008) from Italian individuals or families with HNPCC or CRC, and was not identified in 100 control chromosomes from healthy individuals (Curia 1999, De Lellis 2013, Colombino 2003). Bioinformatic analysis using MAPP-MMR (multivariate analysis of protein polymorphisms) score predicted the variant to be pathogenic (Chao 2008). Allele specific expression of the variant was assayed by comparing cdna/gDNA ratios, and showed a modest level of germline unbalance in allele expression compared to wildtype MSH2 (Curia 1999). The variant was also identified in dbSNP (ID: rs63749879) “With Uncertain significance allele”, ClinVar (classified as uncertain significance, reviewed by an expert panel (2013)), Clinvitae (1x), UMD-LSDB (4x as UV, co-occurring with MSH2 c.2647dup (p.Ile883AsnfsX16)), Insight Colon Cancer Gene Variant Database (5X), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (5x), databases. The variant was not identified in Genesight-COGR, Cosmic, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Val342 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest the Ile variant has 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.;.
Eigen	Benign	0.068
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.36	N;N;.;N
REVEL	Uncertain	0.57
Sift	Benign	0.082	T;T;.;T
Sift4G	Benign	0.096	T;T;.;T
Polyphen		0.039	B;.;.;P
Vest4		0.75
MutPred		0.86		Gain of methylation at K347 (P = 0.0956);.;Gain of methylation at K347 (P = 0.0956);Gain of methylation at K347 (P = 0.0956);
MVP		0.96
MPC		0.0075
ClinPred		0.71	D
GERP RS		4.7
Varity_R		0.16
gMVP		0.20

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: rs63749879; hg19: chr2-47643516;