2-47478309-T-C

Variant names:

• chr2-47478309-T-C
• rs527725593
• NM_000251.3:c.2248T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000251.3(MSH2):​c.2248T>C​(p.Leu750Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,106 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L750L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.08
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-47478309-T-C is Benign according to our data. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47478309-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 219939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2248T>C	p.Leu750Leu	synonymous_variant	Exon 14 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2248T>C	p.Leu750Leu	synonymous_variant	Exon 14 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251402 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461760 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152346 Hom.: 0 Cov.: 31 AF XY: 0.0000268 AC XY: 2 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Jun 28, 2016

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. -

Feb 13, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1

Dec 12, 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. -

Lynch syndrome Benign:1

Oct 06, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 30, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MSH2 c.2248T>C (p.Leu750Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not significantly affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 6 of 121332 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.000303 (5/16500). This frequency is nearly equivalent to the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is may be a benign polymorphism found primarily in the populations of South Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Benign:1

Dec 19, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

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	-0.68
CADD	Benign	6.4
DANN	Benign	0.71
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs527725593; hg19: chr2-47705448; COSMIC: COSV99254667;