2-47403246-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP3BP4_ModerateBP6

The NM_000251.3(MSH2):ā€‹c.55T>Cā€‹(p.Phe19Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000925 in 1,599,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00057 ( 0 hom., cov: 33)
Exomes š‘“: 0.000042 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

11
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:13

Conservation

PhyloP100: 7.36
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.14656064).
BP6
Variant 2-47403246-T-C is Benign according to our data. Variant chr2-47403246-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182595.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=4, Likely_benign=8}. Variant chr2-47403246-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH2NM_000251.3 linkc.55T>C p.Phe19Leu missense_variant Exon 1 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.55T>C p.Phe19Leu missense_variant Exon 1 of 16 1 NM_000251.3 ENSP00000233146.2 P43246-1

Frequencies

GnomAD3 genomes
AF:
0.000571
AC:
87
AN:
152264
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00210
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000110
AC:
24
AN:
219030
Hom.:
0
AF XY:
0.0000837
AC XY:
10
AN XY:
119524
show subpopulations
Gnomad AFR exome
AF:
0.00175
Gnomad AMR exome
AF:
0.0000323
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000422
AC:
61
AN:
1447130
Hom.:
0
Cov.:
31
AF XY:
0.0000348
AC XY:
25
AN XY:
718710
show subpopulations
Gnomad4 AFR exome
AF:
0.00156
Gnomad4 AMR exome
AF:
0.0000475
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:
9.04e-7
Gnomad4 OTH exome
AF:
0.0000835
GnomAD4 genome
AF:
0.000571
AC:
87
AN:
152382
Hom.:
0
Cov.:
33
AF XY:
0.000497
AC XY:
37
AN XY:
74520
show subpopulations
Gnomad4 AFR
AF:
0.00209
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000106
Hom.:
0
Bravo
AF:
0.000620
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000199
AC:
24

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:13
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Lynch syndrome 1 Uncertain:2Benign:2
Mar 19, 2022
Johns Hopkins Genomics, Johns Hopkins University
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Dec 02, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

Dec 18, 2015
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4
Apr 27, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Jan 27, 2025
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The missense variant NM_000251.3(MSH2):c.55T>C (p.Phe19Leu) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. There is a small physicochemical difference between phenylalanine and leucine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.Phe19Leu missense variant is predicted to be damaging by both SIFT and PolyPhen2. The phenylalanine residue at codon 19 of MSH2 is conserved in all mammalian species. The nucleotide c.55 in MSH2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Benign -

Nov 01, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jan 02, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1Benign:2
Oct 25, 2021
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.55T>C, in exon 1 that results in an amino acid change, p.Phe19Leu. This sequence change does not appear to have been previously described in individuals with MSH2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.20% in the African subpopulation (dbSNP rs141711342). The p.Phe19Leu change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Phe19Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Phe19Leu change remains unknown at this time. -

Oct 07, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MSH2 c.55T>C (p.Phe19Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 219030 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.55T>C has been reported in the literature in individuals affected with Colorectal Cancer (e.g. Thompson_2013) and breast cancer (e.g. Maxwell_2014) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.1624C>T, p.Gln542X), providing supporting evidence for a benign role. At least one publication reports the variant as non-pathogenic based on a genetic screen that assesses the MMR-abrogating effect of endogenously expressed Msh2 variants in mESCs (example, Houlleberghs_2016). The following publications have been ascertained in the context of this evaluation (PMID: 22949387, 25503501, 26951660, 30998989). ClinVar contains an entry for this variant (Variation ID: 182595). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 15, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

MSH2-related disorder Benign:1
Feb 11, 2022
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Breast and/or ovarian cancer Benign:1
Jan 12, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary nonpolyposis colon cancer Benign:1
Aug 22, 2023
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Apr 27, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25503501, 22949387, 25256751) -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Feb 03, 2025
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
0.99
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;.;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Uncertain
0.72
D
MutationAssessor
Uncertain
2.9
M;.;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-4.7
D;.;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;.;D
Sift4G
Pathogenic
0.0
D;.;D
Polyphen
1.0
D;.;D
Vest4
0.85
MutPred
0.76
Gain of disorder (P = 0.2072);Gain of disorder (P = 0.2072);Gain of disorder (P = 0.2072);
MVP
0.92
MPC
0.033
ClinPred
0.30
T
GERP RS
5.5
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Varity_R
0.96
gMVP
0.59

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: rs141711342; hg19: chr2-47630385; API