2-47476448-C-T

Position:

• chr2-47476448-C-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.2087C>T​(p.Pro696Leu) 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 (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 7.57

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 16 ACMG points.

• PM1: In a strand (size 8) in uniprot entity MSH2_HUMAN there are 7 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, 0.991
• PP5: Variant 2-47476448-C-T is Pathogenic according to our data. Variant chr2-47476448-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 90881.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476448-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2087C>T	p.Pro696Leu	missense_variant	13/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2087C>T	p.Pro696Leu	missense_variant	13/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Pro696Leu variant has been reported in 2 of 350 proband chromosomes meeting either the Amsterdam criteria for HNPCC or had a suggestive family history associated with a MSI phenotype in the tumor. None of the 600 control chromosomes tested had the variant (Tang_2009_19419416;Tournier_2008_18561205). The variant has also been reported in the UMD (x2) and LOVD (x8) databases. The p.Pro696 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Pro696Leu variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In one study, the tumor harboring the variant was associated with a loss of MSH2 protein expression & high level of MSI in tumors (Tang_2009_19419416). However, in another study, functional analysis using ex vivo splicing assay demonstrated that this variant had no effect (Tournier_2008_18561205). In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. This variant is classified as a variant of unknown significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 07, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 27629256, 26951660]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

Multifactorial likelihood analysis posterior probability >0.99 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 696 of the MSH2 protein (p.Pro696Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 12624141, 19419416, 23729658, 26053027). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90881). 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. Experimental studies have shown that this missense change affects MSH2 function (PMID: 26951660, 27629256, 29731845). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2021

The p.P696L pathogenic mutation (also known as c.2087C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2087. The proline at codon 696 is replaced by leucine, an amino acid with similar properties. This mutation was reported in a Taiwanese individual whose family history met Amsterdam II criteria for Lynch syndrome and tumor displayed loss of MSH2 protein expression by immunohistochemistry as well as high microsatellite instability (MSI-H) (Tang R et al. Clin. Genet., 2009 Apr;75:334-45; Kamiza AB et al. PLoS One, 2015 Jun;10:e0130018). This variant was also reported to segregate in two affected individuals of a French family (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13) and has been identified in individuals either meeting Amsterdam criteria or whose tumors demonstrate absent staining of MSH2 and MSH6 by IHC (Ambry internal data). In two different functional studies, this alteration showed reduced MSH2 protein expression and deficient mismatch repair activity compared to wild type (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33; Tricarico R et al. Hum. Mutat. 2017 Jan;38:64-77) and also demonstrated reduced MSH2 and MSH6 protein interaction in a yeast two-hybrid assay (Zhang X et al. Oncol Lett. 2018 May;15(5):6275-82) In an in vitro complementation assay, this variant was determined to be functionally deficient (Drost M et al. Genet Med, 2019 07;21:1486-1496). This variant was not reported in population-based 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 alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.34	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	0.82	D
PROVEAN	Pathogenic	-9.6	D;D;.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		1.0
MutPred		0.97		Loss of loop (P = 0.2237);.;Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);
MVP		0.97
MPC		0.035
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267607994; hg19: chr2-47703587;