rs775464903

Variant names:

• chr2-47478381-A-G
• rs775464903
• NM_000251.3:c.2320A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-47478381-A-G
• chr2-47478381-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000251.3(MSH2):​c.2320A>G​(p.Ile774Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 5.62

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47478381-A-G is Pathogenic according to our data. Variant chr2-47478381-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408475.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2320A>G	p.Ile774Val	missense_variant	Exon 14 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2320A>G	p.Ile774Val	missense_variant	Exon 14 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 06, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Pathogenic:1

May 19, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 774 of the MSH2 protein (p.Ile774Val). 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: 28765196; external communication, internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 408475). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect MSH2 function (PMID: 33357406). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 16, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I774V pathogenic mutation (also known as c.2320A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2320. The isoleucine at codon 774 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in an individual who met Bethesda, but not Amsterdam criteria, and had osteosarcoma as well as early-onset, mismatch repair deficient rectal cancer displaying loss of MSH2 and MSH6 on immunohistochemistry (IHC) (de Rosa N et al. J. Clin. Oncol., 2016 Sep;34:3039-46; Borras E et al. Cancer Prev. Res. (Phila.), 2017 Oct;10:580-587). This alteration was also identified in several individuals whose family history met Amsterdam I/II criteria for Lynch syndrome and/or colorectal tumor showed loss of MSH2 protein expression by IHC and/or high microsatellite instability (MSI-H) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Lynch syndrome Uncertain:1

Mar 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T;T;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.81	N;N;.;N
REVEL	Uncertain	0.58
Sift	Benign	0.047	D;D;.;D
Sift4G	Benign	0.087	T;T;.;T
Polyphen		0.53	P;.;.;P
Vest4		0.58
MutPred		0.64		Gain of methylation at K773 (P = 0.0531);.;Gain of methylation at K773 (P = 0.0531);Gain of methylation at K773 (P = 0.0531);
MVP		0.87
MPC		0.013
ClinPred		0.79	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.79		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: rs775464903; hg19: chr2-47705520;