rs63750398

Variant names:

• chr2-47476451-G-A
• rs63750398
• NM_000251.3:c.2090G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47476451-G-A
• chr2-47476451-G-C
• chr2-47476451-G-T

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.2090G>A​(p.Cys697Tyr) 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. C697F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• 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 18 ACMG points.

• PM1: In a strand (size 8) in uniprot entity MSH2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr2-47476451-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 2-47476451-G-A is Pathogenic according to our data. Variant chr2-47476451-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187518.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476451-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-47476451-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2090G>A	p.Cys697Tyr	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.2090G>A	p.Cys697Tyr	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: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 31, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C697Y pathogenic mutation (also known as c.2090G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2090. The cysteine at codon 697 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was identified in an individual diagnosed with pancreatic, kidney and colorectal cancers (Langers AMJ et al. Fam Cancer, 2019 07;18:349-352). 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). Another alteration at the same codon, p.C697R (c.2089T>C), has been reported in multiple individuals with personal and/or family history consistent with Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch syndrome, and has been shows to segregate with disease in multiple large families (Wang Q et al. Hum. Genet.; 1999 105:79-85; Isidro G et al. Hum. Mutat., 2000 Jan;15:116; Brieger A et al. Gut, 2002 Nov;51:677-84; Ponz de Leon M et al. Br. J. Cancer, 2004 Feb;90:882-7; Yoon SN et al. Int. J. Cancer, 2008 Mar;122:1077-81; Thodi G et al. BMC Cancer, 2010 Oct;10:544; Pastrello C et al. Genet. Med., 2011 Feb;13:115-24). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, p.C697Y is located in a key structural position and is indicated to be even more structurally destabilizing than the other alterations at this same codon (Ambry internal data). 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 alteration is interpreted as a disease-causing mutation. -

Jan 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with tyrosine at codon 697 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). This variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). In mouse embryonic stem cells, this variant also impacts sensitivity to methylating agents and causes reduced protein expression (PMID: 26951660). This variant has been reported in individuals affected with Lynch syndrome associated cancers (PMID: 31111311; Color internal data), and in an individual undergoing multigene panel testing for hereditary cancer (PMID: 28514183). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same amino acid position, c.2089T>C (p.Cys697Arg) and c.2090G>T (p.Cys697Phe), are considered to be disease-causing (ClinVar variation ID: 90882, 90883), suggesting that the amino acid at this position is important for protein structure and function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 1 Pathogenic:1

Mar 09, 2018

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.987 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 697 of the MSH2 protein (p.Cys697Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic cancer and urothelial carcinoma, as well as an individual undergoing genetic testing for Lynch syndrome (PMID: 28514183, 31111311). ClinVar contains an entry for this variant (Variation ID: 187518). 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%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 6951660). This variant disrupts the p.Cys697 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9298827, 16327991, 17101317, 18951462, 22102614). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.8	H;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-9.4	D;D;.;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.97
MutPred		0.95		Loss of catalytic residue at P696 (P = 0.0079);.;Loss of catalytic residue at P696 (P = 0.0079);Loss of catalytic residue at P696 (P = 0.0079);
MVP		0.95
MPC		0.028
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.98

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: rs63750398; hg19: chr2-47703590; COSMIC: COSV99253152; COSMIC: COSV99253152;