2-47403076-G-A

Variant names:

• chr2-47403076-G-A
• rs587782786
• NM_001258281.1:c.-130G>A

Variant summary

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

The NM_001258281.1(MSH2):​c.-130G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00000115 in 868,030 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: 33)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: MSH2 NM_001258281.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.32
• Publications: 1 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 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258281.1. 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_001258281.1		c.-130G>A		5_prime_UTR	Exon 1 of 17	NP_001245210.1
	MSH2	NM_000251.3	MANE Select	c.-116G>A		upstream_gene	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.-116G>A		upstream_gene	N/A	NP_001393603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000543555.6	TSL:2	c.-130G>A		5_prime_UTR	Exon 1 of 17	ENSP00000442697.1
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.-116G>A		upstream_gene	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.-116G>A		upstream_gene	N/A	ENSP00000384199.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000115 AC: 1 AN: 868030 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 447460

African (AFR) AF: 0.00 AC: 0 AN: 21500

American (AMR) AF: 0.00 AC: 0 AN: 35058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21918

East Asian (EAS) AF: 0.00 AC: 0 AN: 33356

South Asian (SAS) AF: 0.00 AC: 0 AN: 68268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3112

European-Non Finnish (NFE) AF: 0.00000164 AC: 1 AN: 610380

Other (OTH) AF: 0.00 AC: 0 AN: 40826

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.99
PhyloP100		5.3
PromoterAI		-0.41	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.58		Position offset: 1

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

Other links and lift over

dbSNP: rs587782786; hg19: chr2-47630215;