chr2-47429940-A-T

Variant names:

• chr2-47429940-A-T
• rs63751650
• NM_000251.3:c.1275A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001406658.1(MSH2):​c.-82A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_001406658.1 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.9667
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406658.1. 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.1275A>T	p.Glu425Asp	missense splice_region	Exon 7 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406658.1		c.-82A>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 16	NP_001393587.1
	MSH2	NM_001406659.1		c.-82A>T		5_prime_UTR_premature_start_codon_gain	Exon 8 of 17	NP_001393588.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1275A>T	p.Glu425Asp	missense splice_region	Exon 7 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1275A>T	p.Glu425Asp	missense splice_region	Exon 7 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1326A>T	p.Glu442Asp	missense splice_region	Exon 8 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461418 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727060

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111650

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Benign	0.88
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.29	N
REVEL	Uncertain	0.47
Sift	Benign	1.0	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.50
MutPred		0.37		Loss of methylation at K427 (P = 0.0746)
MVP		0.94
MPC		0.0067
ClinPred		0.19	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.15
gMVP		0.20
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.55		Position offset: -47

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs63751650; hg19: chr2-47657079;