NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 9, 2022
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:: RCV000255857.4

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322122	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Feb 3, 2020)	germline	clinical testing	Citation Link,
SCV004222007	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Sep 9, 2022)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 20028993, 24933100, 17718861, 22144684, 24362816, 28514183, 27443514, 33654310, 33888356, 29922827, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000322122

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Feb 3, 2020)

germline

clinical testing

Citation Link,

SCV004222007

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Likely pathogenic
(Sep 9, 2022)

unknown

clinical testing

PubMed (11)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Risks of Lynch syndrome cancers for MSH6 mutation carriers.

Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, Vriends AH; Dutch Lynch Syndrome Study Group., Cartwright NR, Barnetson RA, Farrington SM, Tenesa A, Hampel H, Buchanan D, Arnold S, Young J, Walsh MD, Jass J, Macrae F, Antill Y, Winship IM, Giles GG, et al.

J Natl Cancer Inst. 2010 Feb 3;102(3):193-201. doi: 10.1093/jnci/djp473. Epub 2009 Dec 22.

PubMed [citation]

PMID:: 20028993
PMCID:: PMC2815724

Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for Lynch syndrome.

Batte BA, Bruegl AS, Daniels MS, Ring KL, Dempsey KM, Djordjevic B, Luthra R, Fellman BM, Lu KH, Broaddus RR.

Gynecol Oncol. 2014 Aug;134(2):319-25. doi: 10.1016/j.ygyno.2014.06.009. Epub 2014 Jun 14.

PubMed [citation]

PMID:: 24933100
PMCID:: PMC4125501

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000322122.8

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

Description

In-frame deletion of 1 amino acid in a non-repeat region; Observed in individuals with endometrial, skin, and colorectal cancer, segregating with disease in at least one family, and immunohistochemistry (IHC) of one rectal and one endometrial tumor revealed absence of MSH6 protein (Roncari 2007, Batte 2014, Ring 2016, Ponz de Leon 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 17718861, 24933100, 24763289, 20028993, 24362816, 27443514, 29025352)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004222007.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The frequency of this variant in the general population, 0.000008 (2/251212 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMIDs: 28514183 (2017), 27443514 (2016), and 20028993 (2010)), colorectal cancer (PMIDs: 33654310 (2021) and 17718861 (2007)), and endometrial cancer (PMID: 24933100 (2014)). The variant was found to co-segregate with disease within a family with rectum cancer, colon cancer, endometrial cancer, or polyps (PMID: 17718861 (2007)). Based on the available information, this variant is classified as likely pathogenic.

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

Last Updated: Oct 8, 2024

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