rs63751444

Positions:

• chr2-47410287-T-C
• chr2-47410287-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.560T>C​(p.Leu187Pro) 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. 13/21 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. L187R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.96

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 16 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 chr2-47410287-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 91135.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 2-47410287-T-C is Pathogenic according to our data. Variant chr2-47410287-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 91134.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47410287-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.560T>C	p.Leu187Pro	missense_variant	3/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.560T>C	p.Leu187Pro	missense_variant	3/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 03, 2022	The p.L187P pathogenic mutation (also known as c.560T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 560. The leucine at codon 187 is replaced by proline, an amino acid with similar properties. This mutation has been reported in families meeting Bethesda or Amsterdam criteria and segregated with disease in one family with Muire-Torre phenotype (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Ollila S et al. Int. J. Oncol. 2006 Jan;28:149-53). Published structural analysis suggests that this alteration (L187P) structurally destabalizes the MSH2 protein resulting in reduced binding to MSH3 and MSH6 (Nielsen SV et al. PLoS Genet., 2017 Apr;13:e1006739). In addition, functional assays have shown that the L187P protein is MMR deficient (Ollila S et al. Int. J. Oncol. 2006 Jan;28:149-53; Ollila S et al. Gastroenterology 2006 Nov;131:1408-17; Martinez SL et al. Proc. Natl. Acad. Sci. U.S.A. 2010 Mar;107:5070-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2022	This missense variant replaces leucine with proline at codon 187 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). Functional studies have shown that this variant has deficient DNA repair and tolerance to DNA damaging agents (PMID: 17101317, 20176959, 28422960, 30998989, 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15849733, 17101317, 17192056). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Leu187Pro has been previously has been previously reported by our laboratory in one family with Lynch related tumors and was demonstrated to segregate in three affected individuals and to result in MSH2 immuno-deficiency. In addition, this variant was shown to result in a loss of MSH2 expression by immunohistochemistry and was found to be completely deficient by in vitro MMR activity (Ollila_2006, Ollila_2008, Martinez_2009). One study also classified this variant as deleterious using the multivariate analysis of protein polymorphisms (MAPP)-mismatch repair (MMR) assay (Chao_2008), and a three-step functional analysis model compiling information from the literature has also implicated this as a clinically significant alteration (Kansikas_2010). Another variant at the same amino acid position (p.Leu187Arg) has been documented in the literature in a proband who was MSI +ve and had both colorectal and breast carcinoma (Peel_2000), increasing the likelihood that the p.Leu187Pro variant may have clinical significance. Based on the above information this variant is classified as PATHOGENIC. -

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 14, 2021

- -

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 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 14, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 187 of the MSH2 protein (p.Leu187Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 15849733, 16327991, 17101317, 18951462). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91134). 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: 16327991, 17101317, 18951462, 28422960). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.8	D;D;D;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0030	D;D;D;.;D
Sift4G	Uncertain	0.0080	D;D;D;.;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.98
MutPred		0.95		Gain of disorder (P = 0.0315);.;.;Gain of disorder (P = 0.0315);Gain of disorder (P = 0.0315);
MVP		0.98
MPC		0.029
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.95

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: rs63751444; hg19: chr2-47637426;