2-47466718-G-C

Variant names:

• chr2-47466718-G-C
• rs63751207
• NM_000251.3:c.1571G>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.1571G>C​(p.Arg524Pro) 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. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 9.06

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 2-47466718-G-C is Pathogenic according to our data. Variant chr2-47466718-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1759.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47466718-G-C is described in Lovd as [Likely_pathogenic]. Variant chr2-47466718-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1571G>C	p.Arg524Pro	missense_variant	Exon 10 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1571G>C	p.Arg524Pro	missense_variant	Exon 10 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:3

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 37 year old female diagnosed with colon cancer at age 36. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

Jun 21, 2019

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Abrogated function & 2 MSI-H tumours -

Lynch syndrome 1 Pathogenic:2

Aug 02, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 12124176, 20672385, 28422960]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Sep 27, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Nov 15, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: defective mismatch repair, abolishment of the dominant mutator phenotype, deficient ATPase activity, reduced mismatch-binding in vitro and MNNG-induced chromatin-binding in cells, and decreased MMR protein complex assembly (PMID: 8521394, 9774676, 9889267, 10469597, 12124176, 20672385, 33357406); Observed in patients with Lynch-related cancers (PMID: 15235030, 26845104); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16995940, 14526391, 23741719, 16327991, 28422960, 22290698, 7937795, 8521394, 18383312, 12124176, 9889267, 10469597, 17720936, 9774676, 15340264, 15235030, 17074586, 17594722, 24362816, 16321766, 19062740, 26078562, 21665242, 29345684, 28125613, 12760035, 33357406, 30787465, 18822302, 21120944, 10077621, 34837403, 35583999, 26845104, 20672385, 15849733) -

Jan 18, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.1571G>C (p.Arg524Pro) variant has been reported in the published literature in individuals with Lynch Syndrome (PMIDs: 7937795 (1994), 15235030 (2004)) and Muir-Torre syndrome (PMID: 15849733 (2005)). Additionally, experimental studies have demonstrated a damaging effect on MSH2 protein function (PMID: 7937795 (1994), 8521394 (1995), 10469597 (1999), 12124176 (2002), 17594722 (2007), 17720936 (2007), 20672385 (2010), 33357406 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 31, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with proline at codon 524 in the MSH3/MSH6 interaction and clamp domain of the MSH2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). Functional studies have shown that this variant reduces interactions with MSH3 or MSH6 and impairs mismatch repair (MMR) activities (PMID: 8521394, 12124176, 17594722, 20672385). This variant has been reported in individuals with or suspected with Lynch syndrome (PMID: 15849733, 18931482) and in one individual affected with colorectal cancer (PMID: 26845104). This variant has also been reported in one individual with Muir-Torre syndrome (PMID: 15235030). 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 Likely Pathogenic. -

Jul 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R524P pathogenic mutation (also known as c.1571G>C), located in coding exon 10 of the MSH2 gene, results from a G to C substitution at nucleotide position 1571. The arginine at codon 524 is replaced by proline, an amino acid with dissimilar properties. This alteration was first reported in an individual diagnosed at age 38 with a microsatellite instability high ovarian cancer with loss of heterozygosity (Orth K et al. Proc. Natl. Acad. Sci. U.S.A. 1994 Sep; 91(20):9495-9). This alteration has also been reported in an individual with the Muir-Torre variant of Lynch syndrome and an individual meeting Bethesda criteria (Mangold E et al. J. Med. Genet. 2004 Jul; 41(7):567-72; Shirts BH et al. Genet Med. 2016 Oct;18(10):974-81). This alteration is located in the clamp domain and in vitro DNA binding, ATPase and sliding clamp dissociation studies have shown an effect on the mismatch-dependent molecular switch function of the hMSH2-hMSH6 heterodimer (Heinen CD et al. Cancer Cell 2002 Jun; 1(5):469-78). Multiple functional assays have demonstrated that this protein was repair-deficient, unstable, and unable to elicit a DNA checkpoint in response to DNA alkylation damage (Boyer JC et al. Cancer Res. 1995 Dec; 55(24):6063-70; Mastrocola AS et al. Hum. Mutat. 2010 Oct; 31(10):E1699-708; Nielsen SV et al. PLoS Genet. 2017 Apr 19;13(4):e1006739). 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Jul 29, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.1571G>C (p.Arg524Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, clamp (IPR007861) and DNA mismatch repair protein MutS, core (IPR007696) domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251380 control chromosomes. c.1571G>C has been reported in the literature in individuals affected with Muir-Torre syndrome (e.g. Mangold_2004), ovarian cancer (e.g. Orth_1994), and colon cancer (e.g. Shirts_2016). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g. Drotschmann_1999, Heinen_2002, Gammie_2007, Mastrocola_2010). The most pronounced variant effect results in <10% of normal activity. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 524 of the MSH2 protein (p.Arg524Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 7937795, 15235030, 15849733, 18931482, 26845104; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1759). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 7937795, 10469597, 17594722, 20672385). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.9	D;D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.86		Loss of catalytic residue at R524 (P = 0.0336);.;Loss of catalytic residue at R524 (P = 0.0336);Loss of catalytic residue at R524 (P = 0.0336);
MVP		0.99
MPC		0.031
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs63751207; hg19: chr2-47693857;