rs63751477

Positions:

• chr2-47478306-G-A
• chr2-47478306-G-C
• chr2-47478306-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.2245G>A​(p.Glu749Lys) 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 Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.33

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]

MSH2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a strand (size 5) in uniprot entity MSH2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 2-47478306-G-A is Pathogenic according to our data. Variant chr2-47478306-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90942.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47478306-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-47478306-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2245G>A	p.Glu749Lys	missense_variant	14/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2245G>A	p.Glu749Lys	missense_variant	14/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 08, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 17101317, 18951462, 23690608, 30998989]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16216036, 17101317]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Lynch syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

Abrogated function & 2 MSI-H tumours -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2022

Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 90942). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 12624141, 15849733, 21120944, 21642682; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 749 of the MSH2 protein (p.Glu749Lys). Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 18470917, 18951462, 21120944, 23690608, 30998989). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2024

The p.E749K variant (also known as c.2245G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2245. The glutamic acid at codon 749 is replaced by lysine, an amino acid with similar properties. This variant has been reported in multiple probands meeting Amsterdam and Bethesda criteria (Parc Y et al. J Med Genet. 2003 Mar;40(3):208-13; Mangold E et al. Int J Cancer. 2005 Sep 20;116(5):692-702). In one family meeting Amsterdam criteria, the proband was diagnosed with a microsatellite unstable (MSI-H) colorectal cancer at age 29y and had six family members diagnosed with a Lynch syndrome-associated tumor (Ollila S et al. Gastroenterology. 2006 Nov;131(5):1408-17). In functional studies assessing repair activity, protein stability, mismatch binding, and ATP-catalyzed mismatch release activities, this alteration showed deficient repair and release activity (Ollila S et al. Gastroenterology. 2006 Nov;131(5):1408-17; Ollila S et al. Hum Mutat. 2008 Nov;29(11):1355-63). In addition, in a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.7	D;D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0030	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.98		Gain of methylation at E749 (P = 0.0115);.;Gain of methylation at E749 (P = 0.0115);Gain of methylation at E749 (P = 0.0115);
MVP		0.99
MPC		0.031
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs63751477; hg19: chr2-47705445;