2-47412550-T-C

Variant names:

• chr2-47412550-T-C
• rs63749969
• NM_000251.3:c.782T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP6

The NM_000251.3(MSH2):​c.782T>C​(p.Met261Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,606,302 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. M261I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 7.72
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 21 benign, 30 uncertain in NM_000251.3
• BP6: Variant 2-47412550-T-C is Benign according to our data. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203. Variant chr2-47412550-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 91203.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.782T>C	p.Met261Thr	missense_variant	Exon 4 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.782T>C	p.Met261Thr	missense_variant	Exon 4 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151962 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251096 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454340 Hom.: 0 Cov.: 28 AF XY: 0.00000414 AC XY: 3 AN XY: 723960

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000633 AC: 7 AN: 1105920

Other (OTH) AF: 0.00 AC: 0 AN: 60080

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151962 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74222

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Mar 03, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with threonine at codon 261 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251096 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 Uncertain:1

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with threonine at codon 261 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251096 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 provided Uncertain:1

Mar 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 22949387, 18383312, 26333163, 10348818, 18822302, 21120944) -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Uncertain	0.56	D;.;.;.
Eigen	Benign	-0.058
Eigen_PC	Benign	0.097
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.42	N;.;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	N;N;.;N
REVEL	Uncertain	0.56
Sift	Benign	0.66	T;T;.;T
Sift4G	Benign	0.22	T;T;.;T
Polyphen		0.067	B;.;.;P
Vest4		0.72
MutPred		0.50		Gain of relative solvent accessibility (P = 0.0289);.;Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);
MVP		0.85
MPC		0.014
ClinPred		0.62	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.52
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs63749969; hg19: chr2-47639689;