NM_000179.3(MSH6):c.4001G>C (p.Arg1334Pro) AND Lynch syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 11, 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:: RCV001810439.4

Allele description [Variation Report for NM_000179.3(MSH6):c.4001G>C (p.Arg1334Pro)]

NM_000179.3(MSH6):c.4001G>C (p.Arg1334Pro)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.3

Genomic location:

Preferred name:

NM_000179.3(MSH6):c.4001G>C (p.Arg1334Pro)

HGVS:

NC_000002.12:g.47806651G>C
NG_007111.1:g.28505G>C
NG_008397.1:g.104025C>G
NM_000179.3:c.4001G>CMANE SELECT
NM_001281492.2:c.3611G>C
NM_001281493.2:c.3095G>C
NM_001281494.2:c.3095G>C
NP_000170.1:p.Arg1334Pro
NP_000170.1:p.Arg1334Pro
NP_001268421.1:p.Arg1204Pro
NP_001268422.1:p.Arg1032Pro
NP_001268423.1:p.Arg1032Pro
LRG_219t1:c.4001G>C
LRG_219:g.28505G>C
LRG_219p1:p.Arg1334Pro
NC_000002.11:g.48033790G>C
NM_000179.2:c.4001G>C

Protein change:

R1032P

Links:

dbSNP: rs267608122

NCBI 1000 Genomes Browser:

rs267608122

Molecular consequence:

NM_000179.3:c.4001G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3611G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.3095G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.3095G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002060005	Diagnostic Molecular Genetics Laboratory, Memorial Sloan Kettering Cancer Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 12, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761772	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004024268	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002060005

Diagnostic Molecular Genetics Laboratory, Memorial Sloan Kettering Cancer Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 12, 2022)

germline

clinical testing

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

SCV002761772

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 13, 2022)

germline

clinical testing

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

SCV004024268

Clinical Genetics Laboratory, Skane University Hospital Lund

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 11, 2023)

germline

clinical testing

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

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

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

Details of each submission

From Diagnostic Molecular Genetics Laboratory, Memorial Sloan Kettering Cancer Center, SCV002060005.1

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

Description

The heterozygous germline variant, MSH6 c.4001G>C changes an Arginine to Proline at amino acid position 1334 (p.Arg1334Pro) and affects the last nucleotide of exon 9. This variant is absent from large population databases (1000 Genomes, ESP, and Broad ExAc). Computational prediction tools (SpliceSiteFinder, MaxEntScan, NNSPLICE and GeneSplicer) predict a complete loss of the intron 9 canonical splice donor site. Our functional study by RNA analysis (DMG internal data) demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein. Our results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic.

#	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 Genetics and Molecular Pathology, SA Pathology, SCV002761772.1

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

#	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 Clinical Genetics Laboratory, Skane University Hospital Lund, SCV004024268.1

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

#	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

Last Updated: May 1, 2024

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