2-47476435-G-T

Position:

• chr2-47476435-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.2074G>T​(p.Gly692Trp) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G692R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 9.60

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47476435-G-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 2-47476435-G-T is Pathogenic according to our data. Variant chr2-47476435-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2074G>T	p.Gly692Trp	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.2074G>T	p.Gly692Trp	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/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -

Lynch syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

May 01, 2018

MSH2 NM_000251.2:c.2074G>T has a 96.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. In-silico prediction scores using MAPP and PolyPhen2 give this variant a high likelihood of being pathogenic. This variant has been reported by another laboratory to segregate with Lynch syndrome associated cancers in one family. In addition, a variant at the same position (p.G692R, NM_000179.2:c.2074 G to C) is classified as likely pathogenic (class 4) by the InSiGHT consortium based on case reports and functional analysis. The absence of multiple definitive somatic mutations in MSH2 in tumor is consistent with this variant being pathogenic. Combining all the evidence, this variant is likely pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly692 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10612836, 12624141, 23454724, 23729658, 28577310, 29212164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with Lynch syndrome in a family (external communication). Also, it has been observed in several individuals affected with clinical features of Lynch syndrome (PMID: 28135145, Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 428464). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with tryptophan at codon 692 of the MSH2 protein (p.Gly692Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2021

The p.G692W pathogenic mutation (also known as c.2074G>T), located in coding exon 13 of the MSH2 gene, results from a G to T substitution at nucleotide position 2074. The glycine at codon 692 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been detected as a germline and a somatic mutation in multiple patients with mismatch repair-deficient, MSI-H colorectal cancers (Haraldsdottir S et al. Gastroenterology 2014 Dec;147:1308-1316.e1; Yurgelun MB et al. J Clin Oncol. 2017 Apr 1;35(10):1086-1095; LaDuca H et al. PLoS One. 2017 Feb 2;12(2):e0170843). In addition, using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as likely pathogenic (Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29). Two other alterations at the same codon, p.G692R and p.G692V, have been detected in several Lynch/HNPCC syndrome families with mismatch repair-deficient, MSI-H tumors (Isidro et al. Hum Mut. 2000 Jan; 15(1):116; Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13; Casey G et al. JAMA, 2005 Feb;293:799-809; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Choi YH et al. Hered Cancer Clin Pract, 2009 Aug;7:14; Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463), and the p.G692R alteration has been shown to have reduced protein expression and impaired function (Gammie et al. Genetics. 2007 Oct; 177(2): 707-21; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.7	D;D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.98
MutPred		0.94		Gain of helix (P = 0.2059);.;Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);
MVP		0.98
MPC		0.033
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		0.96

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: rs63750232; hg19: chr2-47703574; COSMIC: COSV51879815; COSMIC: COSV51879815;