chr2-47482945-C-T

Position:

chr2-47482945-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000251.3(MSH2):c.2801C>T(p.Thr934Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,610,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:5

Conservation

PhyloP100: 1.48

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12345126).

BP6

Variant 2-47482945-C-T is Benign according to our data. Variant chr2-47482945-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127641.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.2801C>T	p.Thr934Met	missense_variant	16/16	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.2801C>T	p.Thr934Met	missense_variant	16/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152114

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000566

AC:

AN:

247562

Hom.:

AF XY:

0.0000596

AC XY:

AN XY:

134218

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000996

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000626

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000350

AC:

AN:

1458372

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

725330

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000584

Gnomad4 FIN exome

AF:

0.0000564

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 28, 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	Mar 29, 2023	This missense variant replaces threonine with methionine at codon 934 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer, ovarian cancer, gastrointestinal stromal tumor and unspecified cancer (PMID: 19117025, 26898890, 27498913, 29596542, 31391288, 31569399) with some tumors exhibiting proficient mismatch repair abilities (PMID: 29596542, 31391288). This variant has been reported to occur in affected individuals together with another disease-causing variant in the MLH1 or MSH2 gene that could explain the observed phenotype (ClinVar variation ID: 127641). This variant has been identified in 14/247562 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	curation	Sema4, Sema4	May 05, 2021	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 25, 2022	Variant summary: MSH2 c.2801C>T (p.Thr934Met) results in a non-conservative amino acid change in 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 5.7e-05 in 247562 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (5.7e-05 vs 0.00057), allowing no conclusion about variant significance. c.2801C>T has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with HBOC, colorectal cancer in addition to an individual referred for genetic testing (example, Caminsky_2016, Hampel_2018, Mu_2016, South_2009, Wu_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the UMD database (MLH1 c.2252_2253del, p.Lys751SerfsX3; MSH2 c.1661+1G>T), providing supporting evidence for a benign role. One of these individuals who harbors the co-occuring causal variant in MLH1 is reported as having mismatch repair (MMR) function in tumor cells as MLH1 negative and MSH2 positive which is consistent with the observed variant spectrum. To our knowledge, no other 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. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29596542, 31391288, 26898890, 27720647, 19117025, 27498913, 31569399) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2024	The MSH2 c.2801C>T (p.Thr934Met) variant has been reported in the published literature in individuals affected with breast cancer and ovarian cancer (PMIDs: 19117025 (2009), 26898890 (2016), 31569399 (2019)), as well as in individuals referred for multigene hereditary cancer panel testing (PMID: 27720647 (2016)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). The frequency of this variant in the general population, 0.0001 (3/30122 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Carcinoma of colon

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH2 p.Thr934Met variant was identified in 2 of 728 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome and ovarian cancer (Caminsky 2016, South 2009). The variant was also identified in the following databases: dbSNP (ID: rs587779969 as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹), ClinVar (1x as likely benign by Invitae and 3x uncertain significance by GeneDx, Ambry Genetics, and Color Genomics), UMD-LSDB (5x as neutral), Insight Colon Cancer Gene Variant Database, and Insight Hereditary Tumors Database. The variant was not identified in the COGR, Cosmic, MutDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 14 of 243082 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 14858 chromosomes (freq: 0.0001), Latino in 1 of 33348 chromosomes (freq: 0.00003), European (Non-Finnish) in 7 of 110080 chromosomes (freq: 0.00006), Finnish in 1 of 22236 chromosomes (freq: 0.00005), and South Asian in 3 of 30260 chromosomes (freq: 0.0001); it was not observed in the Other, Ashkenazi Jewish, or East Asian populations. The variant was identified in our lab with a co-occurring pathogenic PMS2 variant (p.Gln719Argfs*6) increasing the likelihood that the p.Thr934Met variant does not have clinical significance. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Thr934 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 05, 2024

This missense variant replaces threonine with methionine at codon 934 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer, ovarian cancer, gastrointestinal stromal tumor and unspecified cancer (PMID: 19117025, 26898890, 27498913, 29596542, 31391288, 31569399) with some tumors exhibiting proficient mismatch repair abilities (PMID: 29596542, 31391288). This variant has been reported to occur in affected individuals together with another disease-causing variant in the MLH1 or MSH2 gene that could explain the observed phenotype (ClinVar variation ID: 127641). This variant has been identified in 14/247562 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. -

Lynch syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

0.12

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.088

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.12

T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.80

N;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

0.021

B;.

Vest4

0.083

MutPred

0.36

Gain of stability (P = 0.0106);.;

MVP

0.71

MPC

0.016

ClinPred

0.057

GERP RS

3.8

Varity_R

0.030

gMVP

0.36

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