rs63751107

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000251.3(MSH2):c.97A>C(p.Thr33Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000587 in 1,601,442 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. T33A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:3

Conservation

PhyloP100: 6.72

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]

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.97A>C	p.Thr33Pro	missense_variant	1/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.97A>C	p.Thr33Pro	missense_variant	1/16	1	NM_000251.3	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000919

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000673

AC:

AN:

222782

Hom.:

AF XY:

0.0000824

AC XY:

AN XY:

121346

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000128

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:

0.000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000552

AC:

AN:

1449182

Hom.:

Cov.:

AF XY:

0.0000472

AC XY:

AN XY:

719814

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000712

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:

0.0000686

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 1

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 21, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2023	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 12, 2022	Variant summary: MSH2 c.97A>C (p.Thr33Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal 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 6.7e-05 in 222782 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (6.7e-05 vs 0.00057), allowing no conclusion about variant significance. c.97A>C has been reported in the literature in individuals affected with Lynch Syndrome, endometrial cancer and colorectal cancer (Hegde_2005, Hampel_2006, Ollila_2006, Chubb_2015, Li_2020, Singh_2020), without strong evidence for causality. Several publications have reported functional studies of the variant showing: normal interaction with MSH6 but decreased in vitro MMR activity (Ollila_2006), weak MMR defect (Martinez_2010), while other pubications reported the variant to be neutral via assays that measured proportions of cells that undergo death following exposure to a methylating agent (Bouvet_2019) and in human cell line models in which MSH2 deletion was complemented by libraries of variants comprising nearly every possible MSH2 missense allele (Jia_2021). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2019	The p.Thr33Pro variant in MSH2 has been reported in 4 individuals with Lynch Syndrome-related cancers (Hedge 2005, Hampel 2006, Ollila 2006, Chubb 2015). Functional studies (microsatellite instability, immunohistochemistry, mismatch repair, expression and interaction assays) provide conflicting evidence on whether the p.Thr33Pro variant impacts protein function (Ollila 2006, Ollila 2008, Kansikas 2011, Martinez 2010). This variant has also been identified in 4/32028 Latino chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Thr33Pro variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, this variant was classified as a variant of uncertain significance on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107811.2). In summary, the clinical significance of the p.Thr33Pro variant is uncertain. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 26, 2022	This alteration is classified as 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 27, 2023	This missense variant replaces threonine with proline at codon 33 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). Functional studies reported this variant as partially functional in mismatch repair assay in vitro (PMID: 17101317) and in yeast (PMID: 20176959). This variant is functional in a methylation tolerance assay (PMID: 30998989) and does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 16237223, 16885385, 17101317, 25559809, 32634176). This variant has been identified in 16/254182 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. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 11, 2024

This missense variant replaces threonine with proline at codon 33 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). Functional studies reported this variant as partially functional in mismatch repair assay in vitro (PMID: 17101317) and in yeast (PMID: 20176959). This variant is functional in a methylation tolerance assay (PMID: 30998989) and does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with rectal cancer (PMID: 25559809) and at least two individuals affected with endometrial cancer (PMID: 16885385, 17101317, 32634176). This variant has been identified in 16/254182 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: interaction with MSH6, expression in colon carcinoma cells, protein stability, mismatch binding, mismatch repair activity, and cell survival similar to wild type (Ollila et al., 2006; Ollila et al., 2008; Martinez et al., 2010; Houlleberghs et al., 2016; Bouvet et al., 2019; Jia et al., 2020); Observed in patients with Lynch-related cancers; however, available tumor studies were inconsistent (Hampel et al., 2006; Ollila et al., 2006; Chubb et al., 2015; Singh et al., 2020); This variant is associated with the following publications: (PMID: 17594722, 17101317, 18951462, 25559809, 22949387, 21120944, 16237223, 16885385, 17370310, 18383312, 20176959, 26951660, 30998989, 33357406, 18822302, 35688932, 32634176, 31391288, 26580448, 32885271) -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH2 p.Thr33Pro variant was identified in 3 of 2424 proband chromosomes (frequency: 0.001) from individuals with colon and endometrial cancer (Hegde 2005, Hampel 2006, Chubb 2015). The variant was identified in dbSNP (rs63751107) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified as "uncertain significance" by Invitae, GeneDx and five other submitters) and UMD-LSDB (observed 2x). The variant was identified in control databases in 14 of 248,976 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 4 of 31,200 chromosomes (freq: 0.0001), European in 10 of 113,324 chromosomes (freq: 0.00009), but not in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. A cell line derived from a patient with the observed variant had normal levels of MSH2 and MSH6 protein as observed on a western blot (Ollila 2006). In an in vitro mismatch repair assay, the variant was generated by site-directed mutagenesis and decreased MMR efficiency by 23% compared to wild type (Ollila 2006). The variant is present in the DNA binding domain of MSH2 and in another study was demonstrated to bind mismatches as efficiently as wild type, and had a slightly reduced DNA release. These observations led to the conclusion that the variant causes a slight defect in MMR efficiency, and based on these experiments, it is unclear if the variant is pathogenic (Ollila 2008). The p.Thr33 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

D;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

3.7

H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.6

D;.;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0030

D;.;D

Polyphen

1.0

D;.;D

Vest4

0.83

MutPred

0.90

Loss of phosphorylation at T33 (P = 0.0579);Loss of phosphorylation at T33 (P = 0.0579);Loss of phosphorylation at T33 (P = 0.0579);

MVP

0.99

MPC

0.032

ClinPred

0.91

GERP RS

3.3

Varity_R

0.99

gMVP

0.84

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over