2-47412543-C-T

Position:

chr2-47412543-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000251.3(MSH2):c.775C>T(p.Pro259Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,606,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:2

Conservation

PhyloP100: 4.78

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 Likely_benign. Variant got -1 ACMG points.

BP6

Variant 2-47412543-C-T is Benign according to our data. Variant chr2-47412543-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140810.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.775C>T	p.Pro259Ser	missense_variant	4/16	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.775C>T	p.Pro259Ser	missense_variant	4/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151582

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251078

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135710

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1455302

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

724354

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:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000994

Gnomad4 OTH exome

AF:

0.0000665

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151582

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74040

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000110

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

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	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 09, 2022	The frequency of this variant in the general population, 0.000004 (1/251078 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMID: 21642682 (2011)), breast cancer (PMID: 26976419 (2016), 33558524 (2021), 32658311 (2021)), and colorectal cancer (PMID: 32658311 (2021)). The variant has also been reported in unaffected individuals (PMID: 33471991 (2021), 31422574 (2019)). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 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 individuals with suspected Lynch syndrome and in individuals with breast cancer (PMID: 21642682, 26976419, 32658311); Published functional studies suggest a neutral effect: demonstrates sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (PMID: 33357406); This variant is associated with the following publications: (PMID: 21642682, 12624141, 26976419, 31391288, 33558524, 32658311, 31422574, 21120944, 18822302, 33357406, 33471991) -

Lynch syndrome 1

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 04, 2023	This missense variant replaces proline with serine at codon 259 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 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 colorectal cancer (PMID: 32658311), breast cancer (PMID: 26976419, 32658311, 33558524), unspecified cancer (PMID: 31391288), and in individuals and families affected with Lynch syndrome (PMID: 12624141, 21642682). This variant has also been observed in healthy controls (PMID: 33471991) and in a healthy individual undergoing genetic testing for hereditary cancer (PMID: 31422574). This variant has been identified in 1/251078 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	Mar 16, 2023	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 29, 2022

Variant summary: MSH2 c.775C>T (p.Pro259Ser) results in a non-conservative amino acid change located in the connector domain (IPR007860) 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 4e-06 in 251078 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.775C>T has been reported in the literature in individuals affected with colorectal cancer / (suspected) Lynch syndrome (e.g. Parc_2003, Bonadona_2011, Li_2020, Akcay_2020) and with breast cancer (e.g. Tung_2016, Akcay_2020, Moradian_2021), however, the variant was also found in healthy controls (Dorling_2021) and in cancer-free individuals undergoing whole-exome sequencing as a secondary finding (Kraemer_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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. -

MSH2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2023

The MSH2 c.775C>T variant is predicted to result in the amino acid substitution p.Pro259Ser. This variant has been reported as a variant of uncertain significance in patients with nonpolyposis colorectal cancer (eTable 1, Bonadona et al. 2011. PubMed ID: 21642682). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47639682-C-T). This variant has been reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/140810/). 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

Mar 24, 2024

This missense variant replaces proline with serine at codon 259 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 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 colorectal cancer (PMID: 32658311), breast cancer (PMID: 26976419, 32658311, 33558524), unspecified cancer (PMID: 31391288), and in individuals and families affected with Lynch syndrome (PMID: 12624141, 21642682). This variant has also been observed in healthy controls (PMID: 33471991) and in a healthy individual undergoing genetic testing for hereditary cancer (PMID: 31422574). This variant has been identified in 1/251078 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. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

Sep 01, 2020

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.5

D;D;.;D

REVEL

Pathogenic

0.74

Sift

Benign

0.043

D;T;.;D

Sift4G

Uncertain

0.057

T;T;.;T

Polyphen

0.73

P;.;.;P

Vest4

0.60

MutPred

0.40

Gain of disorder (P = 0.0626);.;Gain of disorder (P = 0.0626);Gain of disorder (P = 0.0626);

MVP

0.85

MPC

0.0098

ClinPred

0.85

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.43

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