NM_000251.3:c.1121A>T

Variant names:

• chr2-47429786-A-T
• rs749660228
• NM_000251.3:c.1121A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000251.3(MSH2):​c.1121A>T​(p.Gln374Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q374P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.44
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1121A>T	p.Gln374Leu	missense_variant	Exon 7 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1121A>T	p.Gln374Leu	missense_variant	Exon 7 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.5	M;.;.;.
PhyloP100		8.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.1	D;D;.;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0050	D;D;.;D
Sift4G	Uncertain	0.020	D;D;.;D
Polyphen		0.17	B;.;.;B
Vest4		0.76
MutPred		0.42		Loss of disorder (P = 0.0364);.;Loss of disorder (P = 0.0364);Loss of disorder (P = 0.0364);
MVP		0.94
MPC		0.011
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.47
Mutation Taster		=23/77	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: rs749660228; hg19: chr2-47656925;