2-47482858-C-T

Position:

chr2-47482858-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000251.3(MSH2):c.2714C>T(p.Thr905Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. T905R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.936

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02110678).

BP6

Variant 2-47482858-C-T is Benign according to our data. Variant chr2-47482858-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91038.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.2714C>T	p.Thr905Ile	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.2714C>T	p.Thr905Ile	missense_variant	16/16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00230

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:

0.000478

GnomAD3 exomes

AF:

0.0000838

AC:

AN:

250742

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135544

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461160

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

726856

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 19, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH2 p.Thr905Ile variant was identified in 1 of 930 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer and was thought to be a benign germline variant as it was on the allele lost in the tumour of the individual (Hampel 2018). The variant was also identified in dbSNP (ID: rs267608022) as "With Uncertain significance, other allele", in ClinVar (classified as likely benign by Ambry Genetics and Invitae; and as uncertain significance by InSiGHT, GeneDx, and Color Genomics), UMD-LSDB (identified in 1 submission). The variant was identified in control databases in 22 of 276632 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23984 chromosomes (freq: 0.00004), Other in 1 of 6452 chromosomes (freq: 0.0002), European Non-Finnish in 5 of 126396 chromosomes (freq: 0.00004), Ashkenazi Jewish in 15 of 10132 chromosomes (freq: 0.0015); it was not observed in the Latino, East Asian, Finnish, and South Asian populations. The p.Thr905Ile 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect in a cell survival assay (PMID: 30998989); Observed in an individual with colon cancer, but observed on the lost tumor allele suggesting a benign variant (PMID: 29596542); Observed in both cases and controls in a breast cancer case-control study (PMID: 33471991); This variant is associated with the following publications: (PMID: 12124176, 16995940, 25203624, 22290698, 18383312, 26333163, 20459533, 9774676, 26934580, 14526391, 18822302, 21120944, 27720647, 33471991, 36845387, 30998989, 29596542) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 26, 2022	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 24, 2018	Variant summary: The MSH2 c.2714C>T (p.Thr905Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Multiple studies using computational tools predicted variant as benign (Ali_2012, Niroula_2015). This variant was found in 22/276632 control chromosomesc (gnomAD), predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.00148 (15/10132). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. This variant has not been reported in affected individuals via publications; nor has it been evaluated for functional impact via in vitro/vivo studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/uncertain significance. Taken together, this variant is classified as VUS-possibly benign until more evidence becomes available. -

MSH2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Lynch syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 23, 2024

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.65

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.40

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.0010

B;.

Vest4

0.21

MVP

0.94

MPC

0.0064

ClinPred

0.031

GERP RS

2.5

Varity_R

0.079

gMVP

0.18

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