NM_000179.3(MSH6):c.3744_3773del (p.His1248_Ser1257del) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 8, 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:: RCV000491301.6

Allele description [Variation Report for NM_000179.3(MSH6):c.3744_3773del (p.His1248_Ser1257del)]

NM_000179.3(MSH6):c.3744_3773del (p.His1248_Ser1257del)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.3744_3773del (p.His1248_Ser1257del)

HGVS:

NC_000002.12:g.47806301_47806330del
NG_007111.1:g.28155_28184del
NG_008397.1:g.104350_104379del
NM_000179.3:c.3744_3773delMANE SELECT
NM_001281492.2:c.3354_3383del
NM_001281493.2:c.2838_2867del
NM_001281494.2:c.2838_2867del
NP_000170.1:p.His1248_Ser1257del
NP_000170.1:p.His1248_Ser1257del
NP_001268421.1:p.His1118_Ser1127del
NP_001268422.1:p.His946_Ser955del
NP_001268423.1:p.His946_Ser955del
LRG_219t1:c.3744_3773del
LRG_219:g.28155_28184del
LRG_219p1:p.His1248_Ser1257del
NC_000002.11:g.48033436_48033465del
NC_000002.11:g.48033440_48033469del
NM_000179.2:c.3744_3773del
NM_000179.2:c.3744_3773del
NM_000179.2:c.3744_3773del30
NM_000179.2:c.3744_3773del30
NM_000179.2:c.3744_3773delCTACCATTCATTAGTAGAAGATTATTCTCA

Links:

dbSNP: rs863225412

NCBI 1000 Genomes Browser:

rs863225412

Molecular consequence:

NM_000179.3:c.3744_3773del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281492.2:c.3354_3383del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281493.2:c.2838_2867del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001281494.2:c.2838_2867del - 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
SCV000580154	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 21, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17531815, 29710228, 34145315 Citation Link,
SCV004357752	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 8, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 580154, 624910, 29710228, 34145315, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580154

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 21, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004357752

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 8, 2023)

germline

clinical testing

PubMed (5)
[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

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

Glucose and cation transport in rat jejunum, ileum and colon in vivo: control experiments, and effect of cationic surfactant.

Sund RB.

Acta Pharmacol Toxicol (Copenh). 1978 Feb;42(2):117-24.

PubMed [citation]

PMID:: 580154

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000580154.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.3744_3773del30 pathogenic mutation (also known as p.H1248_S1257del) is located in coding exon 8 of the MSH6 gene. This mutation results from an in-frame deletion of 30 nucleotides at positions 3744 to 3773 and causes the removal of 10 well-conserved amino acid residues at codons 1248 to 1257. This mutation has been seen in individuals with Lynch syndrome, including three families meeting Amsterdam criteria with tumor results from one family showing loss of MSH6 protein on immunohistochemistry (Chang K et al. JAMA Oncol, 2018 08;4:1085-1092; Ambry internal data). This mutation was also reported in a woman whose endometrial tumor demonstrated loss of MSH6 on IHC (Dedeurwaerdere F et al. Sci Rep, 2021 06;11:12880). In addition, this mutation segregated with disease in the three families with a combined LOD score of 1.8 (Ambry internal data). Based on internal structural analysis, this alteration results in a distortion of the α-helix of a protein-protein interface of MSH6, significantly altering the surrounding residues (Warren JJ et al. Mol. Cell. 2007 May; 26(4):579-92). 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, SCV004357752.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant causes an in-frame deletion of 10 amino acids at exon 8 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 and Lynch syndrome-associated cancer (PMID: 29710228; ClinVar SCV000580154.5, SCV000624910.8), and in an individual affected with mismatch repair deficient endometrial cancer (PMID: 34145315).This variant has been identified in 1/251206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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: Sep 29, 2024

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