2-47403245-C-T

Variant names:

• chr2-47403245-C-T
• rs63750777
• NM_000251.3:c.54C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_000251.3(MSH2):​c.54C>T​(p.Gly18Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,446,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.810
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 2-47403245-C-T is Benign according to our data. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598. Variant chr2-47403245-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 455598.
• BP7: Synonymous conserved (PhyloP=0.81 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.54C>T	p.Gly18Gly	synonymous_variant	Exon 1 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.54C>T	p.Gly18Gly	synonymous_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446764 Hom.: 0 Cov.: 31 AF XY: 0.00000418 AC XY: 3 AN XY: 718488

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.0000714 AC: 3 AN: 42028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25750

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39142

South Asian (SAS) AF: 0.00 AC: 0 AN: 83692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106430

Other (OTH) AF: 0.00 AC: 0 AN: 59832

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Apr 23, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 21, 2018

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. -

Apr 19, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 16, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Lynch syndrome 1 Benign:1

Dec 02, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		0.81
PromoterAI		0.047	Neutral
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs63750777; hg19: chr2-47630384;