chr2-47476525-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000251.3(MSH2):​c.2164G>T​(p.Val722Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V722I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

10
8
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 9.60
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.2164G>T p.Val722Phe 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.2164G>T p.Val722Phe missense_variant Exon 13 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461886
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3
Nov 29, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

May 10, 2019
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 14, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.V722F variant (also known as c.2164G>T), located in coding exon 13 of the MSH2 gene, results from a G to T substitution at nucleotide position 2164. The valine at codon 722 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was identified in a cohort of early-onset colorectal cancer patients undergoing whole exome sequencing (Thutkawkorapin J et al. Mol Genet Genomic Med, 2019 05;7:e605). 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 neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). 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 available evidence, the clinical significance of this alteration remains unclear. -

Lynch syndrome 1 Uncertain:2
Mar 16, 2023
Myriad Genetics, Inc.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Aug 22, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Apr 11, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MSH2 c.2164G>T (p.Val722Phe) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2164G>T has been reported in the literature in at least one individual affected with early onset colorectal cancer (CRC) (Thutkawkorapin_2019). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1
Feb 25, 2020
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MSH2 c.2164G>T; p.Val722Phe variant (rs587781996), to our knowledge, is not reported in the medical literature, but is reported in the ClinVar database (Variation ID: 408474). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 722 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. A different variant at this codon (p.Val722Ile) is reported in the literature in an individual with Lynch syndrome (Lagerstedt-Robinson 2016), and in an individual with breast/ovarian cancer but this individual also carried a pathogenic frameshift BRCA2 variant (Dominguez-Valentin 2018). Due to limited information, the clinical significance of the p.Val722Phe variant is uncertain at this time. REFERENCES Dominguez-Valentin M et al. Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds. Hered Cancer Clin Pract. 2018 Jan 15;16:4. Lagerstedt-Robinson K et al. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. Oncol Rep. 2016 Nov;36(5):2823-2835. -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Jun 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.79
D;.;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.88
D;D;D;D
MetaSVM
Uncertain
0.70
D
MutationAssessor
Uncertain
2.7
M;.;.;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-4.1
D;D;.;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0010
D;D;.;D
Sift4G
Uncertain
0.0030
D;D;.;D
Polyphen
1.0
D;.;.;D
Vest4
0.89
MutPred
0.57
Loss of catalytic residue at V722 (P = 0.1287);.;Loss of catalytic residue at V722 (P = 0.1287);Loss of catalytic residue at V722 (P = 0.1287);
MVP
0.94
MPC
0.032
ClinPred
0.99
D
GERP RS
6.2
Varity_R
0.86
gMVP
0.95

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: rs587781996; hg19: chr2-47703664; API