2-47445592-A-C

Position:

chr2-47445592-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000251.3(MSH2):c.1321A>C(p.Thr441Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,374 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: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:2O:1

Conservation

PhyloP100: 1.25

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 0 ACMG points.

PM1

In a helix (size 18) in uniprot entity MSH2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000251.3

BP4

Computational evidence support a benign effect (MetaRNN=0.19821554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1321A>C	p.Thr441Pro	missense_variant	8/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.1321A>C	p.Thr441Pro	missense_variant	8/16	1	NM_000251.3	ENSP00000233146	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250898

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135718

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:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1461190

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726958

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:

0.0000531

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000918

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2023	Observed in individuals with colorectal, pancreatic, ovarian, and breast cancer (Niessen et al., 2006; Chao et al., 2008; Pal et al., 2012; Maxwell et al., 2015); Published functional studies demonstrate slightly reduced protein expression, normal sensitivity to DNA damage, and stable microsatellite instability analysis (Rath et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26333163, 22290698, 18383312, 25503501, 23047549, 16636019, 33357406, 31237724, 18822302, 21120944) -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Likely benign and reported on 08-03-2020 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 08, 2023	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 15, 2019	The MSH2 c.1321A>C; p.Thr441Pro variant (rs587779086) is reported in the literature in multiple individuals affected with colorectal, ovarian, and breast cancer (Chao 2008, Maxwell 2015, Pal 2012). This variant is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variation ID: 90628), and is found in the non-Finnish European population with an allele frequency of 0.005% (7/128884 alleles) in the Genome Aggregation Database. The threonine at codon 441 is weakly conserved, and computational analyses (Ali 2012, SIFT, PolyPhen-2) predict that this variant is tolerated. Due to conflicting information, the clinical significance of the p.Thr441Pro variant is uncertain at this time. References Ali H et al. Classification of mismatch repair gene missense variants with PON-MMR. Hum Mutat. 2012 Apr;33(4):642-50. Chao EC et al. Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat. 2008 Jun;29(6):852-60. Maxwell KN et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. 2015 Aug;17(8):630-8. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 21, 2021	Variant summary: MSH2 c.1321A>C (p.Thr441Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein mut S, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1321A>C has been reported in the literature in individuals affected with MSI-low colorectal cancer and one patient with positive IHC staining for MLH1 and MSH2 (Chao_2008, Niessen_2006), early onset breast cancer (Maxwell_2014), epithelial ovarian cancer (Pal_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on measures of protein stability, DNA repair function and damage response signaling in an experimental system using CRISPR Cas9 gene editing to engineer VUS in human embryonic cells (Rath_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=5). Some submitters, to include one classifying the variant as likely benign utilize overlapping functional and other evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 13, 2023	This missense variant replaces threonine with proline at codon 441 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant rescued MSH2-deficient human embryonic stem cells (PMID: 31237724) and had intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been observed in individuals affected with Lynch syndrome-associated cancers (PMID: 16636019, 18383312, 23047549) for which tumors in two carriers showed mismatch repair-proficient characteristics (PMID: 16636019, 18383312). This variant also has been reported in an individual affected with breast cancer (PMID: 25503501). This variant has been identified in 7/282308 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 submitter	curation	Sema4, Sema4	Jul 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 17, 2020	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. -

MSH2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2024

The MSH2 c.1321A>C variant is predicted to result in the amino acid substitution p.Thr441Pro. This variant has been reported in association with multiple cancer types including pancreatic (Niessen et al. 2006. PubMed ID: 16636019, sup. table 1), breast (Maxwell et al. 2015. PubMed ID: 25503501, sup. table 1), ovarian (Pal et al. 2012. PubMed ID: 23047549, sup. table 1, Niessen et al. 2006. PubMed ID: 16636019, sup. table 1) and colon cancer (Chao et al. 2008. PubMed ID: 18383312). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/90628/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 27, 2022

- -

Lynch syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces threonine with proline at codon 441 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant rescued MSH2-deficient human embryonic stem cells (PMID: 31237724) and had intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been observed in individuals affected with Lynch syndrome-associated cancers (PMID: 16636019, 18383312, 23047549) for which tumors in two carriers showed mismatch repair-proficient characteristics (PMID: 16636019, 18383312). This variant also has been reported in an individual affected with breast cancer (PMID: 25503501). This variant has been identified in 7/282308 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. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;.;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Benign

0.051

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.6

L;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.5

N;N;.;N

REVEL

Uncertain

0.57

Sift

Benign

0.058

T;D;.;T

Sift4G

Benign

0.066

T;T;.;T

Polyphen

0.011

B;.;.;B

Vest4

0.76

MVP

1.0

MPC

0.0082

ClinPred

0.064

GERP RS

1.9

Varity_R

0.67

gMVP

0.45

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