chr2-47476391-C-G

Position:

• chr2-47476391-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000233146.7(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 Conflicting classifications of pathogenicity (no stars). 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 ENST00000233146.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications 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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 14 uncertain in ENST00000233146.7
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 233888.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2030C>G	p.Thr677Arg	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.2030C>G	p.Thr677Arg	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 23, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2024	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:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 11, 2019	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. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been observed in individuals affected with rectal cancer (PMID: 22086678, 27432916). 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 a Variant of Uncertain Significance. -

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

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

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; Invitae). ClinVar contains an entry for this variant (Variation ID: 233888). 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%. 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;.;.;.
MutationTaster	Benign	1.0	D;D;D
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

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