rs1064794561

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000233146.7(MSH2):ā€‹c.2519T>Cā€‹(p.Val840Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V840I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

MSH2
ENST00000233146.7 missense

Scores

11
7
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.39
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH2NM_000251.3 linkuse as main transcriptc.2519T>C p.Val840Ala missense_variant 15/16 ENST00000233146.7 NP_000242.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkuse as main transcriptc.2519T>C p.Val840Ala missense_variant 15/161 NM_000251.3 ENSP00000233146 P1P43246-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251446
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461824
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 10, 2019This missense variant replaces valine with alanine at codon 840 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 12, 2023The p.V840A variant (also known as c.2519T>C), located in coding exon 15 of the MSH2 gene, results from a T to C substitution at nucleotide position 2519. The valine at codon 840 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Lynch syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJun 06, 2023- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 17, 2018This variant is denoted MSH2 c.2519T>C at the cDNA level, p.Val840Ala (V840A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Val840Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Val840Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 840 of the MSH2 protein (p.Val840Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 420561). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D;.;.;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
D;D;D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.96
D;D;D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Uncertain
2.8
M;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-3.9
D;D;.;D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0020
D;D;.;D
Sift4G
Pathogenic
0.0
D;D;.;D
Polyphen
1.0
D;.;.;D
Vest4
0.95
MutPred
0.83
Gain of disorder (P = 0.0865);.;Gain of disorder (P = 0.0865);Gain of disorder (P = 0.0865);
MVP
0.95
MPC
0.033
ClinPred
0.99
D
GERP RS
5.9
Varity_R
0.92
gMVP
0.76

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1064794561; hg19: chr2-47707895; API