chr2-47478342-G-A

Position:

• chr2-47478342-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.2281G>A​(p.Gly761Arg) 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. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G761E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.33

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 20 ACMG points.

• PS1: Transcript NM_000251.3 (MSH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 483671
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 16 uncertain 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 chr2-47478343-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2095532.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 2-47478342-G-A is Pathogenic according to our data. Variant chr2-47478342-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 408557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2281G>A	p.Gly761Arg	missense_variant	14/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2281G>A	p.Gly761Arg	missense_variant	14/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 08, 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2022

This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 408557). This missense change has been observed in individuals with Lynch syndrome (Invitae). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 761 of the MSH2 protein (p.Gly761Arg). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2022

The p.G761R variant (also known as c.2281G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2281. The glycine at codon 761 is replaced by arginine, an amino acid with dissimilar properties. 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). The yeast equivalent of this variant demonstrated an increased mutation rate in a multiplexed functional assay performed using Saccharomyces cerevisiae (Ollodart AR et al. Genetics, 2021 06;218:). The p.G761R variant (c.2281G>C) has been reported in one individual undergoing genetic testing for colorectal cancer predisposition (Rey JM et al. J Mol Diagn, 2017 Jul;19:589-601). This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of MSH6 expression by immunohistochemistry (Ambry internal data). 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 majority of available evidence to date, this variant is likely to be 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	0.43
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.4	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.5	D;D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.92		Gain of methylation at G761 (P = 0.0671);.;Gain of methylation at G761 (P = 0.0671);Gain of methylation at G761 (P = 0.0671);
MVP		0.98
MPC		0.033
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502038; hg19: chr2-47705481;