NM_000251.3(MSH2):c.174dup (p.Lys59fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 9, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001180218.5

Allele description [Variation Report for NM_000251.3(MSH2):c.174dup (p.Lys59fs)]

NM_000251.3(MSH2):c.174dup (p.Lys59fs)

Gene:

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.174dup (p.Lys59fs)

HGVS:

NC_000002.12:g.47403365dup
NG_007110.2:g.5242dup
NM_000251.3:c.174dupMANE SELECT
NM_001258281.1:c.-25dup
NP_000242.1:p.Lys59fs
LRG_218t1:c.174dup
LRG_218:g.5242dup
NC_000002.11:g.47630503_47630504insC
NC_000002.11:g.47630504dup
NC_000002.12:g.47403364_47403365insC
NM_000251.1:c.174dupC
NM_000251.2:c.174dup

Protein change:

K59fs

Links:

dbSNP: rs1672250622

NCBI 1000 Genomes Browser:

rs1672250622

Molecular consequence:

NM_001258281.1:c.-25dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000251.3:c.174dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001345088	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 9, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002711632	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 5, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21681552, 24344984 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001345088

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 9, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002711632

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 5, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals.

Valentin MD, da Silva FC, dos Santos EM, Lisboa BG, de Oliveira LP, Ferreira Fde O, Gomy I, Nakagawa WT, Aguiar Junior S, Redal M, Vaccaro C, Valle AD, Sarroca C, Carraro DM, Rossi BM.

Fam Cancer. 2011 Dec;10(4):641-7. doi: 10.1007/s10689-011-9461-y.

PubMed [citation]

PMID:: 21681552

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001345088.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant inserts 1 nucleotide in exon 1 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been observed in three suspected Lynch syndrome families, with one proband affected with colon cancer and sebaceous carcinoma before age 50 (PMID: 26437257, 28874130). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002711632.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.174dupC pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a duplication of C at nucleotide position 174, causing a translational frameshift with a predicted alternate stop codon (p.K59Qfs*23). This alteration has been reported in Brazilian families meeting Bethesda or Amsterdam criteria and has been referred to as c.175dup in published literature (Valentin MD et al. Fam. Cancer, 2011 Dec;10:641-7; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2013 Dec;11:18). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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