rs200252727

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBP6

The NM_000251.3(MSH2):c.2354A>C(p.His785Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,182 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).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2

Conservation

PhyloP100: 8.90

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 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

BP6

Variant 2-47478415-A-C is Benign according to our data. Variant chr2-47478415-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185569.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2354A>C	p.His785Pro	missense_variant	14/16	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.2354A>C	p.His785Pro	missense_variant	14/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152214

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251450

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135896

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:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000999

AC:

146

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727220

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:

0.000128

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74488

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2021	Variant summary: MSH2 c.2354A>C (p.His785Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251450 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (4.8e-05 vs 0.00057), allowing no conclusion about variant significance. c.2354A>C has been reported in the literature in individuals affected with colon cancer and breast cancer (example, Chubb_2015, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least one co-occurrence with another pathogenic variant has been reported (Chubb_2015, POLD1 c.1433G>A, p.Ser478Asn), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. 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	Nov 17, 2016	The p.His785Pro variant in MSH2 has been reported in 1 individual with colorecta l cancer; however, this patient also harbored a likely disease causing variant i n the POLD1 gene (Chubb et al 2015; POLD1, Ser478Asn: Palles 2013). The His785Pr o variant has been identified in 2/66730 European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200252727). Com putational prediction tools and conservation analysis suggest that the p.His785P ro variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, the clinical significance of the p.H is785Pro variant is uncertain. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 30, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2019	This variant is denoted MSH2 c.2354A>C at the cDNA level, p.His785Pro (H785P) at the protein level, and results in the change of a Histidine to a Proline (CAT>CCT). This variant has been identified in at least one individual with a personal and family history of colorectal cancer, co-occurring with a POLD1 variant (Chubb 2015). MSH2 His785Pro was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 His785Pro occurs at a position that is conserved across species and is located in the ATPase domain (LÃ¼tzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 His785Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2023	This missense variant replaces histidine with proline at codon 785 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: 25559809), breast cancer (PMID: 25186627) and kidney renal clear cell carcinoma (PMID: 29684080). This variant has been identified in 14/282842 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. -

MSH2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2024

The MSH2 c.2354A>C variant is predicted to result in the amino acid substitution p.His785Pro. This variant has been reported in an individual with colorectal cancer; however, this individual also had a likely pathogenic variant in POLD1 (Table A1 - Chubb et al. 2015. PubMed ID: 25559809). This variant has also been reported in individuals with breast cancer (Tung N et al. 2014. PubMed ID: 25186627) or renal cancer (Yehia L et al. 2018. PubMed ID: 29684080). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity of likely benign and uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/185569/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 02, 2024

- -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Apr 16, 2024

This missense variant replaces histidine with proline at codon 785 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: 25559809), breast cancer (PMID: 25186627) and kidney renal clear cell carcinoma (PMID: 29684080). This variant has been identified in 14/282842 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

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;.;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Uncertain

-0.0062

MutationAssessor

Uncertain

2.8

M;.;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-9.7

D;D;.;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Uncertain

0.0030

D;D;.;D

Polyphen

1.0

D;.;.;D

Vest4

0.97

MVP

0.98

MPC

0.030

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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