2-47466747-C-T

Position:

chr2-47466747-C-T

Variant summary

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

The NM_000251.3(MSH2):c.1600C>T(p.Arg534Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,656 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. R534H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 2.06

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP6

Variant 2-47466747-C-T is Benign according to our data. Variant chr2-47466747-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90707.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.1600C>T	p.Arg534Cys	missense_variant	10/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.1600C>T	p.Arg534Cys	missense_variant	10/16	1	NM_000251.3	P1	P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152102

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:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251364

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74300

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:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 1

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 25, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 05, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 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]. -

Lynch syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces arginine with cysteine 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). Functional studies have shown conflicting results regarding the impact of this variant on mRNA splicing (PMID: 16995940, 18561205). This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 18561205), and an individual affected with an unspecified cancer (PMID: 31391288). This variant has also been reported in a healthy individual lacking personal or family history of colorectal cancer (PMID: 26344056). This variant has been identified in 2/282752 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	University of Washington Department of Laboratory Medicine, University of Washington	May 01, 2018	MSH2 NM_000251.2:c.1600C>T has a 76.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 26, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 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 an individual reported to have HNPCC, but was also observed in a control population without personal or family history of colorectal cancer (Tournier et al., 2008; Arora et al., 2015); Mini-gene splicing assays have shown this variant to cause partial or complete skipping of exon 10 (Lastella et al., 2006; Tournier et al., 2008); This variant is associated with the following publications: (PMID: 16995940, 22290698, 18561205, 9490293, 26344056, 30798936, 18822302, 9774676, 21120944, 34426522, 31391288, 14526391, 29887214) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 2022	The p.R534C variant (also known as c.1600C>T), located in coding exon 10 of the MSH2 gene, results from a C to T substitution at nucleotide position 1600. The arginine at codon 534 is replaced by cysteine, an amino acid with highly dissimilar properties. A report in the literature suggests that this variant may have an effect on pre-mRNA splicing, by altering exonic splicing regulatory sequences. Additionally, this alteration was transfected into three different mammalian cell lines and a decrease in the exon inclusion levels in two of the three cell lines was seen (Lastella P et al. BMC Genomics. 2006 Sep;7:243). This alteration has also been reported to affect splicing by functional analysis using the ESE-dependent splicing assay (Tournier I et al. Hum. Mutat. 2008 Dec;29:1412-24). RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This variant was identified in a tumor with LOH of MSH2, but authors suggested classifying as VUS following multifactorial analysis (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 18, 2023	This missense variant replaces arginine with cysteine 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). Functional studies have shown conflicting results regarding the impact of this variant on mRNA splicing (PMID: 16995940, 18561205). This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 18561205), and an individual affected with an unspecified cancer (PMID: 31391288). This variant has also been reported in a healthy individual lacking personal or family history of colorectal cancer (PMID: 26344056). This variant has been identified in 2/282752 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 specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 23, 2024

Variant summary: MSH2 c.1600C>T (p.Arg534Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. A functional study showed a decrease in inclusion of exon 10 in an in-vitro mini-gene assay perfromed in several cell lines (Lastella_2006). The variant allele was found at a frequency of 4e-06 in 251364 control chromosomes. c.1600C>T has been reported in the literature in individuals affected with cancer and in controls (example, Gorlov_2003, Arora_2015, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 26344056, 14526391, 16995940, 31391288, 18561205). ClinVar contains an entry for this variant (Variation ID: 90707). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.69

D;D;D;D

MetaSVM

Uncertain

-0.063

MutationAssessor

Pathogenic

3.3

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.7

D;D;.;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Pathogenic

0.0

D;D;.;D

Polyphen

1.0

D;.;.;D

Vest4

0.81

MutPred

0.57

Loss of solvent accessibility (P = 0.0079);.;Loss of solvent accessibility (P = 0.0079);Loss of solvent accessibility (P = 0.0079);

MVP

0.94

MPC

0.031

ClinPred

1.0

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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