NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 10, 2023
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:: RCV000129144.15

Allele description [Variation Report for NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del)]

NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del)

Gene:

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del)

HGVS:

NC_000002.12:g.47806281_47806283del
NG_007111.1:g.28135_28137del
NG_008397.1:g.104395_104397del
NM_000179.3:c.3724_3726delMANE SELECT
NM_001281492.2:c.3334_3336del
NM_001281493.2:c.2818_2820del
NM_001281494.2:c.2818_2820del
NP_000170.1:p.Arg1242del
NP_001268421.1:p.Arg1112del
NP_001268422.1:p.Arg940del
NP_001268423.1:p.Arg940del
LRG_219:g.28135_28137del
NC_000002.11:g.48033418_48033420del
NC_000002.11:g.48033420_48033422del
NM_000179.2:c.3724_3726delCGT
p.R1242del

Protein change:

R1112del

Links:

dbSNP: rs63749942

NCBI 1000 Genomes Browser:

rs63749942

Molecular consequence:

NM_000179.3:c.3724_3726del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281492.2:c.3334_3336del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281493.2:c.2818_2820del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281494.2:c.2818_2820del - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV000183865	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17718861, 20028993, 24933100, 27443514 Citation Link,
SCV000690391	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 10, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 183865, 17718861, 20028993, 24362816, 24933100, 27443514, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000183865

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 15, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000690391

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 10, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Effects of ergosterol on bone mineralisation in chicks given cholecalciferol or ergocalciferol.

Webb GP, Taylor TG.

Br Poult Sci. 1976 Sep;17(5):509-12.

PubMed [citation]

PMID:: 183865

Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCC.

Roncari B, Pedroni M, Maffei S, Di Gregorio C, Ponti G, Scarselli A, Losi L, Benatti P, Roncucci L, De Gaetani C, Camellini L, Lucci-Cordisco E, Tricarico R, Genuardi M, Ponz de Leon M.

Clin Genet. 2007 Sep;72(3):230-7.

PubMed [citation]

PMID:: 17718861

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000183865.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.3724_3726delCGT pathogenic mutation (also known as p.R1242del) is located in coding exon 8 of the MSH6 gene. This variant results from an in-frame CGT deletion at nucleotide positions 3724 to 3726. This results in the in-frame deletion of an arginine at codon 1242. This alteration was identified in an individual diagnosed with an MSH6-deficient rectal cancer at age 42 and a family history meeting the Amsterdam II criteria; this same alteration was present in this individual's brother, who was diagnosed with rectal cancer at age 53, and mother, who was diagnosed with endometrial cancer at age 54 and ascending colon cancer at age 78 (Roncari B et al. Clin. Genet. 2007 Sep;72:230-7). This alteration has also been reported in multiple other patients with a personal and/or family history consistent with Lynch syndrome, including several demonstrating loss of MSH6 protein by immunohistochemistry (IHC) analysis (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Batte BA et al. Gynecol. Oncol. 2014 Aug;134(2):319-25; Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389; Ambry internal data). In addition, a missense variant impacting codon 1242 (p.R1242H) has been detected in trans with a pathogenic MSH6 mutation in an individual whose clinical presentation was consistent with CMMR-D due to biallelic MSH6 mutations and had isolated absence of MSH6 in both tumor and normal tissue by IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, 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

From Color Diagnostics, LLC DBA Color Health, SCV000690391.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant causes a deletion of the conserved arginine at codon 1242 located in the ATPase domain of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 20028993; ClinVar SCV000183865.7), colorectal cancer (PMID: 17718861), and endometrial cancer (PMID: 24933100, 27443514). This variant has been shown to segregate with colorectal cancer in three members of a family (PMID: 17718861). Loss of MSH6 protein expression has been observed in tumor tissues from two affected carriers (PMID: 17718861, 24933100). This variant has also been observed in an individual affected with constitutional mismatch repair deficiency who carried a pathogenic MSH6 variant in trans (ClinVar SCV000183865.7). A multifactorial likelihood analysis using genetic data, computational prediction and tumor pathology has indicated that this variant has a high probability of being pathogenic (PMID: 24362816). This variant has been identified in 2/251212 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Missense variants occurring at this codon, p.Arg1242His and p.Arg1242Ser, are thought to be disease-causing (Clinvar variation ID: 140866, 89449), indicating the importance of arginine at this codon for MSH6 protein function. Based on the 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

Last Updated: Oct 8, 2024

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