2-47410089-C-T

Variant names:

• chr2-47410089-C-T
• rs587782414
• NM_000251.3:c.367-5C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_000251.3(MSH2):​c.367-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MSH2 NM_000251.3 splice_region, intron
• Scores: Splicing: ADA: 0.00007992
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.192
• 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: Benign. The variant received -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-47410089-C-T is Benign according to our data. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410089-C-T is described in CliVar as Likely_benign. Clinvar id is 142372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.367-5C>T		splice_region_variant, intron_variant	Intron 2 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.367-5C>T		splice_region_variant, intron_variant	Intron 2 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459802 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726204

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 85850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110974

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Benign:1

Dec 04, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Aug 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jan 03, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.9
DANN	Benign	0.43
PhyloP100		-0.19

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.018
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: rs587782414; hg19: chr2-47637228;