rs548407418

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6

The NM_000251.3(MSH2):c.1790A>C(p.Asp597Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D597G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:4

Conservation

PhyloP100: 8.51

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 1 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 15 uncertain in NM_000251.3

BP6

Variant 2-47475055-A-C is Benign according to our data. Variant chr2-47475055-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 183758.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Benign=1, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1790A>C	p.Asp597Ala	missense_variant	12/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.1790A>C	p.Asp597Ala	missense_variant	12/16	1	NM_000251.3	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.000478

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251456

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

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:

0.000163

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461422

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000112

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00105

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:

0.000473

Bravo

AF:

0.000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 23, 2020	The MSH2 c.1790A>C (p.Asp597Ala) missense change has a maximum subpopulation frequency of 0.0087% gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-47702194-A-C). In silico tools are not in agreement about a tolerated or damaging effect on the gene or protein product and functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces aspartic acid with alanine at codon 597 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). A functional study reported that this variant may not impact DNA mismatch repair activity based on a 6-thioguanine sensitivity assay in Msh2-deficient haploid human cells (PMID: 33357406). This variant has been reported in one individual affected with pediatric leukemia (PMID: 26580448), an individual affected with an unspecified Lynch syndrome-associated cancer (PMID: 31391288), and in a healthy control (PMID: 33471991). This variant has been identified in 4/251456 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:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a pediatric patient with leukemia and in an individual whose tumor was assessed with MSI and/or IHC (Zhang et al., 2015; Li et al., 2020); Published functional studies suggest a neutral effect: demonstrates resistance to 6-TG similar to wild type (Jia et al., 2020); This variant is associated with the following publications: (PMID: 31569399, 33471991, 18822302, 9774676, 21120944, 26580448, 33357406, 31391288) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	The frequency of this variant in the general population, 0.000087 (3/34586 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with Lynch syndrome-associated cancer and acute lymphoblastic leukemia (PMIDs: 31391288 (2020) and 26580448 (2015)). In a large case-control study, this variant has only been detected in an unaffected control but not in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). A screening assay based on cell survival in response to 6-thioguanine treatment indicated the variant has neutral effects on DNA mismatch repair function in vivo (PMID: 33357406 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 26, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 04, 2023	This missense variant replaces aspartic acid with alanine at codon 597 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). A functional study reported that this variant may not impact DNA mismatch repair activity based on a 6-thioguanine sensitivity assay in Msh2-deficient haploid human cells (PMID: 33357406). This variant has been reported in one individual affected with pediatric leukemia (PMID: 26580448), an individual affected with an unspecified Lynch syndrome-associated cancer (PMID: 31391288), and in a healthy control (PMID: 33471991). This variant has been identified in 4/251456 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 12, 2021	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. -

Lynch syndrome 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 12, 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: 27363726]. -

MSH2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2024

The MSH2 c.1790A>C variant is predicted to result in the amino acid substitution p.Asp597Ala. This variant has been reported in an individual with hypodiploid acute lymphoblastic leukemia (Table S4A, Zhang et al. 2015. PubMed ID: 26580448). In addition, this variant is observed once and interpreted as variant of uncertain significance in a cohort study of 4740 patients with Lynch syndrome associated cancer (Table S5, Li et al 2020. PubMed ID: 31391288). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183758/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 08, 2023

Variant summary: MSH2 c.1790A>C (p.Asp597Ala) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 150914 control chromosomes, predominantly at a frequency of 0.001 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.8-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1790A>C has been reported in the literature in individuals affected with pediatric leukemia and Lynch syndrome-associated cancer (Zhang_2015, Li_2020), but was also found among healthy controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the variant restores 6-thioguanine sensitivity, thus likely does not impact DNA mismatch repair activity (Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 26580448, 31569399, 31391288, 33357406, 33471991). Ten other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=8), likely benign (n=1) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.49

T;.;.;.

Eigen

Benign

-0.080

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.4

L;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.4

D;D;.;D

REVEL

Pathogenic

0.69

Sift

Benign

0.77

T;T;.;T

Sift4G

Benign

0.80

T;T;.;T

Polyphen

0.0020

B;.;.;B

Vest4

0.78

MutPred

0.53

Gain of glycosylation at T594 (P = 0.3232);.;Gain of glycosylation at T594 (P = 0.3232);Gain of glycosylation at T594 (P = 0.3232);

MVP

0.97

MPC

0.016

ClinPred

0.72

GERP RS

5.6

Varity_R

0.51

gMVP

0.74

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