2-47429789-C-G

Variant names:

• chr2-47429789-C-G
• rs774539871
• NM_000251.3:c.1124C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000233146.7(MSH2):​c.1124C>G​(p.Thr375Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T375I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 ENST00000233146.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0870
• Publications: 3 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12841192).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000233146.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.1124C>G	p.Thr375Ser	missense	Exon 7 of 16	NP_000242.1
	MSH2	NM_001406674.1		c.1124C>G	p.Thr375Ser	missense	Exon 7 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.1124C>G	p.Thr375Ser	missense	Exon 7 of 18	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1124C>G	p.Thr375Ser	missense	Exon 7 of 16	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.1124C>G	p.Thr375Ser	missense	Exon 7 of 16	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.1124C>G	p.Thr375Ser	missense	Exon 7 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	2.9
DANN	Benign	0.78
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.13	N
PhyloP100		0.087
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.94	N
REVEL	Uncertain	0.34
Sift	Benign	0.39	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.35		Gain of phosphorylation at T375 (P = 0.054)
MVP		0.78
MPC		0.0067
ClinPred		0.069	T
GERP RS		-1.5
Varity_R		0.16
gMVP		0.089
Mutation Taster		=96/4	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: rs774539871; hg19: chr2-47656928;