NM_000251.3:c.2013T>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000251.3(MSH2):​c.2013T>A​(p.Asn671Lys) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N671D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MSH2
NM_000251.3 missense

Scores

11
7
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 0.0340
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 Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 14 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 chr2-47476373-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1784432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.971
PP5
Variant 2-47476374-T-A is Pathogenic according to our data. Variant chr2-47476374-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90858.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}. Variant chr2-47476374-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.2013T>A p.Asn671Lys missense_variant Exon 13 of 16 ENST00000233146.7 NP_000242.1 P43246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSH2ENST00000233146.7 linkc.2013T>A p.Asn671Lys missense_variant Exon 13 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1
Aug 07, 2023
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23690608]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided Pathogenic:1
Jan 10, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1
Sep 21, 2023
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.N671K variant (also known as c.2013T>A), located in coding exon 13 of the MSH2 gene, results from a T to A substitution at nucleotide position 2013. The asparagine at codon 671 is replaced by lysine, an amino acid with similar properties. This alteration demonstrated deficient mismatch repair activity in a cellular-based functional assay using human/mouse expression systems (Drost M et al. Proc Natl Acad Sci U S A, 2013 Jun;110:9403-8). 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 Jan;108:163-175). This alteration was detected in an individual with MMR-deficient early-onset colon cancer amongst a cohort of 372 unrelated individuals undergoing genetic testing for Lynch syndrome (LS) based on a personal and/or family history of LS-associated cancers (Henriksson I et al. J Community Genet, 2019 Apr;10:259-266). This alteration was also identified in an individual diagnosed with colorectal cancer at 45 (Rohlin A et al. Fam Cancer, 2017 Apr;16:195-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Oct 28, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 671 of the MSH2 protein (p.Asn671Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MSH2-related conditions (PMID: 18383312, 30251116). ClinVar contains an entry for this variant (Variation ID: 90858). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) 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: 23690608). 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
1.0
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;.;.;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Pathogenic
0.54
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Pathogenic
4.6
H;.;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-5.5
D;D;.;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0010
D;D;.;D
Sift4G
Pathogenic
0.0
D;D;.;D
Polyphen
1.0
D;.;.;D
Vest4
0.97
MutPred
0.93
Loss of ubiquitination at K675 (P = 0.0368);.;Loss of ubiquitination at K675 (P = 0.0368);Loss of ubiquitination at K675 (P = 0.0368);
MVP
0.97
MPC
0.032
ClinPred
1.0
D
GERP RS
2.4
Varity_R
0.96
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

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

Other links and lift over

dbSNP: rs587779127; hg19: chr2-47703513; API