chr2-47478478-C-G

Variant names:

• chr2-47478478-C-G
• rs758889557
• NM_000251.3:c.2417C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP3 BP6

The NM_000251.3(MSH2):​c.2417C>G​(p.Thr806Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,792 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. T806I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.49
• Publications: 2 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 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 35 uncertain in NM_000251.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781
• BP6: Variant 2-47478478-C-G is Benign according to our data. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534. Variant chr2-47478478-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1418534.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2417C>G	p.Thr806Ser	missense_variant	Exon 14 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2417C>G	p.Thr806Ser	missense_variant	Exon 14 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251392 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461792 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111972

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T806S variant (also known as c.2417C>G), located in coding exon 14 of the MSH2 gene, results from a C to G substitution at nucleotide position 2417. The threonine at codon 806 is replaced by serine, 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 highly 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. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 18, 2022

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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.6	L;.;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D;D;.;D
REVEL	Uncertain	0.60
Sift	Benign	0.20	T;T;.;T
Sift4G	Uncertain	0.056	T;T;.;D
Polyphen		0.98	D;.;.;D
Vest4		0.76
MutPred		0.49		Gain of disorder (P = 0.0766);.;Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);
MVP		0.83
MPC		0.033
ClinPred		0.90	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.63
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758889557; hg19: chr2-47705617;