NM_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 15, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000128906.13

Allele description [Variation Report for NM_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del)]

NM_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del)

HGVS:

NC_000002.12:g.47804953CTG[1]
NG_007111.1:g.26807CTG[1]
NG_008397.1:g.105718CAG[1]
NM_000179.3:c.3482CTG[1]MANE SELECT
NM_001281492.2:c.3092CTG[1]
NM_001281493.2:c.2576CTG[1]
NM_001281494.2:c.2576CTG[1]
NP_000170.1:p.Ala1162del
NP_001268421.1:p.Ala1032del
NP_001268422.1:p.Ala860del
NP_001268423.1:p.Ala860del
LRG_219t1:c.3485_3487del
LRG_219:g.26807CTG[1]
NC_000002.11:g.48032092CTG[1]
NC_000002.11:g.48032092_48032094del
NM_000179.2:c.3485_3487del
NM_000179.2:c.3485_3487delCTG
NM_000179.3:c.3485_3487delMANE SELECT
p.A1162del

Protein change:

A1032del

Links:

dbSNP: rs63751427

NCBI 1000 Genomes Browser:

rs63751427

Molecular consequence:

NM_000179.3:c.3482CTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281492.2:c.3092CTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281493.2:c.2576CTG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281494.2:c.2576CTG[1] - 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
SCV000172773	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely pathogenic (Mar 15, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12732731, 17531815, 23056405, 34667028 Citation Link,
SCV000908422	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 14, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 172773, 22658618, 28514183, 28888541, 34667028, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000172773

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Likely pathogenic
(Mar 15, 2023)

germline

clinical testing

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

Citation Link,

SCV000908422

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 14, 2022)

germline

clinical testing

PubMed (6)
[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

Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers.

Goodfellow PJ, Buttin BM, Herzog TJ, Rader JS, Gibb RK, Swisher E, Look K, Walls KC, Fan MY, Mutch DG.

Proc Natl Acad Sci U S A. 2003 May 13;100(10):5908-13. Epub 2003 May 5.

PubMed [citation]

PMID:: 12732731
PMCID:: PMC156300

Structure of the human MutSalpha DNA lesion recognition complex.

Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS.

Mol Cell. 2007 May 25;26(4):579-92.

PubMed [citation]

PMID:: 17531815

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000172773.9

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

Description

The c.3485_3487delCTG variant (also known as p.A1162del) is located in coding exon 6 of the MSH6 gene. This variant results from an in-frame CTG deletion at nucleotide positions 3485 to 3487. This results in the in-frame deletion of an alanine at codon 1162. This alteration has been identified in three individuals with endometrial cancer and ages at diagnosis ranged from 45y to 54y. One of the individuals was also diagnosed with rectal cancer at the age of 60y. Tumor results for two of the individuals revealed loss of MSH6 protein expression on immunohistochemistry (IHC) while the third individual had a family history that met Amsterdam criteria (Ambry internal data). The alteration was also reported in a patient with endometrial cancer and rectal cancer diagnosed at the ages of 53y and 61y, respectively. Furthermore, tumor results from the endometrial cancer revealed microsatellite instability (MSI-H) (Goodfellow PJ et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100(10: 5908-13). This alteration has also been reported in an individual with a personal history of uterine and breast cancers, and family history of uterine, colon and breast cancers (Schwartz CJ et al. Clin Cancer Res, 2022 Jan;28:404-413). The alanine residue resides in a well-defined functional domain and is adjacent to a helix that contains the MSH6 ATP binding p-loop (Warren JJ et al. Mol. Cell 2007 May;26(4):579-92). This amino acid position is highly conserved in available vertebrate species and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE 2012 ; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be 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 Color Diagnostics, LLC DBA Color Health, SCV000908422.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant is an in-frame deletion of an alanine in the the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer, uterine, colorectal, breast cancer, and Lynch syndrome (PMID: 22658618, 28514183, 28888541, 34667028, ClinVar: SCV000172773). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Feb 20, 2024

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