2-47403322-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2 PP3_Strong BP6

The NM_000251.3(MSH2):​c.131C>T​(p.Thr44Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 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. T44K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• BP6: Variant 2-47403322-C-T is Benign according to our data. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627. Variant chr2-47403322-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 90627.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.131C>T	p.Thr44Met	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>T	p.Thr44Met	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: 0.00

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453272 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722234

African (AFR) AF: 0.00 AC: 0 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: 0.000178 AC: 1 AN: 5606

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109674

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T44M variant (also known as c.131C>T), located in coding exon 1 of the MSH2 gene, results from a C to T substitution at nucleotide position 131. The threonine at codon 44 is replaced by methionine, an amino acid with similar properties. This alteration was detected in a colorectal cancer family but not fulfilling the Amsterdam criteria (Bisgaard ML et al. Hum Mutat, 2002 Jul;20:20-7). This alteration has demonstrated mismatch repair (MMR) activity similar to wild-type or benign controls in functional studies from multiple independent laboratories (Gammie AE et al. Genetics, 2007 Oct;177:707-21; Christensen LL et al. Fam Cancer, 2009 Aug;8:489-500; Martinez SL et al. Proc Natl Acad Sci U S A, 2010 Mar;107:5070-5; Drost M et al. Hum Mutat, 2012 Mar;33:488-94). A study of the functional significance of MSH2 missense variants using CRISPR-Cas9 gene editing in human embryonic stem cells suggests this alteration is proficient at DNA repair function, damage response signaling and protein stability (Rath A et al. Hum Mutat, 2019 11;40:2044-2056). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Nov 03, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jul 20, 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	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.6	H;.;.
PhyloP100		7.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.6	D;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.74
MutPred		0.92		Loss of phosphorylation at T44 (P = 0.0647);Loss of phosphorylation at T44 (P = 0.0647);Loss of phosphorylation at T44 (P = 0.0647);
MVP		0.97
MPC		0.031
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.15	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.94
gMVP		0.69
Mutation Taster		=22/78	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;