chr2-47403322-C-A

Variant names:

• chr2-47403322-C-A
• rs587779085
• NM_000251.3:c.131C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_Moderate BP6

The NM_000251.3(MSH2):​c.131C>A​(p.Thr44Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,453,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T44M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.26
• Publications: 8 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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• BP6: Variant 2-47403322-C-A is Benign according to our data. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872. Variant chr2-47403322-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 142872.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.131C>A	p.Thr44Lys	missense_variant	Exon 1 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.131C>A	p.Thr44Lys	missense_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000438 AC: 1 AN: 228568 AF XY: 0.00

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: 0.00000977

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1453272 Hom.: 0 Cov.: 31 AF XY: 0.00000554 AC XY: 4 AN XY: 722234

African (AFR) AF: 0.0000299 AC: 1 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 43202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.00 AC: 0 AN: 84390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00000811 AC: 9 AN: 1109674

Other (OTH) AF: 0.00 AC: 0 AN: 60050

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Jun 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with lysine at codon 44 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). 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 1/228568 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. -

Mar 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T44K variant (also known as c.131C>A), located in coding exon 1 of the MSH2 gene, results from a C to A substitution at nucleotide position 131. The threonine at codon 44 is replaced by lysine, an amino acid with similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Lynch syndrome 1 Uncertain:1

Nov 17, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.6	H;.;.
PhyloP100		7.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	D;.;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0030	D;.;D
Polyphen		0.99	D;.;D
Vest4		0.75
MutPred		0.67		Gain of methylation at T44 (P = 0.0231);Gain of methylation at T44 (P = 0.0231);Gain of methylation at T44 (P = 0.0231);
MVP		0.94
MPC		0.031
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.0038	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.99
gMVP		0.79
Mutation Taster		=17/83	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: rs587779085; hg19: chr2-47630461;