2-47476391-C-G

Variant names:

• chr2-47476391-C-G
• rs876660711
• NM_000251.3:c.2030C>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.2030C>G​(p.Thr677Arg) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T677A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.57
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 29 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 2-47476391-C-G is Pathogenic according to our data. Variant chr2-47476391-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 233888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2030C>G	p.Thr677Arg	missense_variant	Exon 13 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2030C>G	p.Thr677Arg	missense_variant	Exon 13 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 23, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.2030C>G (p.Thr677Arg) variant has been reported in the published literature in individuals with rectal cancer (PMID: 22086678 (2012), 27432916 (2016)). Published functional studies show that this variant is damaging to protein function (PMID: 33357406 (2021), 33848333 (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 pathogenic. -

Aug 09, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in an individual with early-onset rectal cancer whose tumor displayed mismatch repair deficiency on immunohistochemistry and another individual with rectal cancer whose tumor demonstrated microsatellite instability (MSI-H) and normal protein expression on immunohistochemistry (PMID: 27432916, 22086678); 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: 27432916, 22086678, 22208277, 28765196, 16214425, 17531815, 30787465, 33848333, 36550560, 33357406, 18822302, 21120944) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 30, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T677R pathogenic mutation (also known as c.2030C>G), located in coding exon 13 of the MSH2 gene, results from a C to G substitution at nucleotide position 2030. The threonine at codon 677 is replaced by arginine, an amino acid with similar properties. This variant has been identified in probands whose colorectal tumors demonstrated high microsatellite instability (MSI-H) and isolated loss of MSH6 expression by immunohistochemistry (IHC) was also seen in one of the tumors (Ambry internal data). This variant was reported in an individual diagnosed with mismatch repair-deficient rectal cancer at age 45 whose personal and family history met Bethesda guidelines, but not Amsterdam I or II criteria (de Rosa N et al. J. Clin. Oncol., 2016 Sep;34:3039-46). This variant was also reported in a 48 year old individual with MSI-H rectal cancer that demonstrated intact mismatch repair protein expression by IHC and had no family history of a Lynch syndrome–associated cancers (Bartley AN et al. Cancer Prev Res (Phila), 2012 Feb;5:320-7). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). The yeast equivalent of this variant also demonstrated increased mutation rates in a multiplexed functional assay performed using Saccharomyces cerevisiae (Ollodart AR et al. Genetics, 2021 Jun;218:). Based on internal structural analysis, p.T677R introduces a large, charged side-chain into the ATP-binding pocket of MSH2, a region sensitive to alteration (Ambry internal data; Antony E et al. DNA Repair (Amst), 2006 Feb;5:153-62; Warren JJ et al. Mol Cell, 2007 May;26:579-92). 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 alteration is interpreted as a disease-causing mutation. -

Nov 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with arginine at codon 677 of the MSH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. This variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (ClinGen VCEP defined LOF score threshold > 0.4, PMID: 33357406). The yeast equivalent of this variant demonstrated significantly increased mutation rate in Saccharomyces cerevisiae (PMID: 33848333). This variant has been observed in individuals affected with colorectal cancer that displayed high microsatellite instability but intact MSH2 protein via immunohistochemistry (PMID: 22086678), as well as an individual affected with colorectal cancer whose immunohistochemistry analysis showed loss of mismatch repair protein (PMID: 27432916). This variant has also been reported in individuals affected with Lynch syndrome-associated disease that displayed high microsatellite instability and/or loss of MSH6 protein via immunohistochemistry (ClinVar SCV000278353.6). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as Pathogenic. -

Lynch syndrome 1 Pathogenic:1

Aug 07, 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: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 677 of the MSH2 protein (p.Thr677Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 22086678, 27432916; internal data). ClinVar contains an entry for this variant (Variation ID: 233888). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;.;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.6	D;D;.;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.97
MutPred		0.86		Gain of MoRF binding (P = 0.025);.;Gain of MoRF binding (P = 0.025);Gain of MoRF binding (P = 0.025);
MVP		0.99
MPC		0.034
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		0.99
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs876660711; hg19: chr2-47703530; COSMIC: COSV51875820;