2-47463076-C-A

Variant names:

• chr2-47463076-C-A
• rs1051194508
• NM_000251.3:c.1432C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000251.3(MSH2):​c.1432C>A​(p.Leu478Ile) 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 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. L478F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.491
• 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: ClinGen, Orphanet, G2P
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 30 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47463077-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1772564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.1432C>A	p.Leu478Ile	missense	Exon 9 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1432C>A	p.Leu478Ile	missense	Exon 9 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.1432C>A	p.Leu478Ile	missense	Exon 9 of 18	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1432C>A	p.Leu478Ile	missense	Exon 9 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1432C>A	p.Leu478Ile	missense	Exon 9 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1483C>A	p.Leu495Ile	missense	Exon 10 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		0.49
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.63		Loss of disorder (P = 0.1503)
MVP		0.88
MPC		0.034
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.88
gMVP		0.46
Mutation Taster		=66/34	polymorphism

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: rs1051194508; hg19: chr2-47690215;