rs587778523

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6

The NM_000251.3(MSH2):c.1601G>A(p.Arg534His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,738 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). Synonymous variant affecting the same amino acid position (i.e. R534R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:2O:1

Conservation

PhyloP100: 9.06

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:

MSH2 (HGNC:):

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

BP6

Variant 2-47466748-G-A is Benign according to our data. Variant chr2-47466748-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127632.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1601G>A	p.Arg534His	missense_variant	10/16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.1601G>A	p.Arg534His	missense_variant	10/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251348

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135858

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:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461640

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727124

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:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000823

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Jul 17, 2017	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 21, 2023	This missense variant replaces arginine with histidine at codon 534 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). This variant has 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 reported in individuals affected with colorectal cancer (PMID: 25142776, 29684080), breast cancer (PMID: 33471991), and esophageal squamous cell carcinoma (PMID: 31396961), but also in healthy individuals (PMID: 24728327, 33471991). This variant has been identified in 14/251348 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	clinical testing	Ambry Genetics	Jun 12, 2024	The p.R534H variant (also known as c.1601G>A), located in coding exon 10 of the MSH2 gene, results from a G to A substitution at nucleotide position 1601. The arginine at codon 534 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a 68-year-old male patient with colorectal cancer; however this individuals tumor exhibited normal IHC and was MSS (Kraus C et al. Int J Cancer, 2015 Mar;136:E559-68). Another study reported this alteration in a cohort of Chinese esophageal squamous cell carcinoma patients (Ko JM et al. Int J Cancer, 2020 02;146:1042-1051). This variant was reported in 7/60,466 breast cancer cases but also reported in 6/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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 01;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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lynch syndrome 1

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 14, 2016	- -
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]. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate mismatch repair function similar to wildtype (PMID: 33357406); Observed in an individual with colorectal cancer whose tumor showed normal immunohistochemistry results and had microsatellite stability (PMID: 25142776); This variant is associated with the following publications: (PMID: 24728327, 28494185, 18822302, 9774676, 21120944, 26824983, 33471991, 31396961, 34326862, 29684080, 33357406, 25142776) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 07, 2024	The MSH2 c.1601G>A (p.Arg534His) variant has been reported in the published literature in individuals with colorectal cancer (PMIDs: 25142776 (2015), 28494185 (2017)), breast cancer (34326862 (2021), 33471991 (2021), see LOVD (https://databases.lovd.nl/shared/)), and esophageal cancer (PMID: 31396961 (2020)). This variant has also been observed in reportedly healthy individuals (PMIDs: 23012121 (2012), 24728327 (2014), 33471991 (2021), see LOVD (https://databases.lovd.nl/shared/)). A cell-survival screening assay suggests this variant has neutral effects on DNA mismatch repair function (PMID: 33357406 (2021)). The frequency of this variant in the general population, 0.000098 (3/30606 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2018	Variant summary: MSH2 c.1601G>A (p.Arg534His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, clamp domain (IPR007861), which is inserted between the two subdomains of the core domain. 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 5.3e-05 in 246194 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (5.3e-05 vs 0.00057), allowing no conclusion about variant significance. c.1601G>A has been reported in the literature in individuals affected with colorectal cancer and in an individual with a positive family history of inherited cancer disorder (Kraus_2015, O'Leary_2014). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH2 c.998G>A, p.Cys333Tyr (LOVD)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

MSH2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2024

The MSH2 c.1601G>A variant is predicted to result in the amino acid substitution p.Arg534His. This variant has been reported in individuals with colorectal cancer (Kraus et al. 2015. PubMed ID: 25142776; Yehia et al. 2018. PubMed ID: 29684080), breast cancer (Bhai et al. 2021. PubMed ID: 34326862), and esophageal cancer (Ko et al. 2019. PubMed ID: 31396961). However, this variant was present at similar frequencies in a large cohort of breast cancer patients (n = 7; 0.12%) compared to unaffected controls (n = 6; 0.011%) (Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991) and was classified as "functionally neutral" based on the results of a high-throughput DNA damage repair assay (Jia et al. 2021. PubMed ID: 33357406). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD and is classified as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127632/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 30, 2023

This missense variant replaces arginine with histidine at codon 534 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). This variant has 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 reported in individuals affected with colorectal cancer (PMID: 25142776, 29684080), breast cancer (PMID: 33471991), and esophageal squamous cell carcinoma (PMID: 31396961), but also in healthy individuals (PMID: 24728327, 33471991). This variant has been identified in 14/251348 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

Likely 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

0.91

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.3

M;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.7

D;D;.;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

D;D;.;D

Sift4G

Uncertain

0.0020

D;D;.;D

Polyphen

1.0

D;.;.;D

Vest4

0.76

MutPred

0.52

Loss of MoRF binding (P = 0.0235);.;Loss of MoRF binding (P = 0.0235);Loss of MoRF binding (P = 0.0235);

MVP

0.93

MPC

0.032

ClinPred

0.96

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.88

gMVP

0.60

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