NM_000179.3(MSH6):c.4004A>C (p.Glu1335Ala) AND Lynch syndrome 5

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 29, 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:: RCV000409369.5

Allele description [Variation Report for NM_000179.3(MSH6):c.4004A>C (p.Glu1335Ala)]

NM_000179.3(MSH6):c.4004A>C (p.Glu1335Ala)

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.4004A>C (p.Glu1335Ala)

HGVS:

NC_000002.12:g.47806781A>C
NG_007111.1:g.28635A>C
NG_008397.1:g.103895T>G
NM_000179.3:c.4004A>CMANE SELECT
NM_001281492.2:c.3614A>C
NM_001281493.2:c.3098A>C
NM_001281494.2:c.3098A>C
NP_000170.1:p.Glu1335Ala
NP_000170.1:p.Glu1335Ala
NP_001268421.1:p.Glu1205Ala
NP_001268422.1:p.Glu1033Ala
NP_001268423.1:p.Glu1033Ala
LRG_219t1:c.4004A>C
LRG_219:g.28635A>C
LRG_219p1:p.Glu1335Ala
NC_000002.11:g.48033920A>C
NM_000179.2:c.4004A>C
p.E1335A

Protein change:

E1033A

Links:

dbSNP: rs564434147

NCBI 1000 Genomes Browser:

rs564434147

Molecular consequence:

NM_000179.3:c.4004A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3614A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.3098A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.3098A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Lynch syndrome 5 (LYNCH5)
Synonyms:: Colorectal cancer, hereditary nonpolyposis, type 5; Hereditary non-polyposis colorectal cancer, type 5
Identifiers:: MONDO: MONDO:0013710; MedGen: C1833477; Orphanet: 144; OMIM: 614350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000489131	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Aug 25, 2016)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23523604, 24073290 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV001135869	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV004018961	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely benign (Mar 29, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000489131

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Aug 25, 2016)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV001135869

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV004018961

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely benign
(Mar 29, 2023)

unknown

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Evaluating the effect of unclassified variants identified in MMR genes using phenotypic features, bioinformatics prediction, and RNA assays.

Pérez-Cabornero L, Infante M, Velasco E, Lastra E, Miner C, Durán M.

J Mol Diagn. 2013 May;15(3):380-90. doi: 10.1016/j.jmoldx.2013.02.003. Epub 2013 Mar 20.

PubMed [citation]

PMID:: 23523604

Integrated analysis of mismatch repair system in malignant astrocytomas.

Rodríguez-Hernández I, Garcia JL, Santos-Briz A, Hernández-Laín A, González-Valero JM, Gómez-Moreta JA, Toldos-González O, Cruz JJ, Martin-Vallejo J, González-Sarmiento R.

PLoS One. 2013;8(9):e76401. doi: 10.1371/journal.pone.0076401.

PubMed [citation]

PMID:: 24073290
PMCID:: PMC3779191

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000489131.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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

From Mendelics, SCV001135869.1

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

#	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

From Myriad Genetics, Inc., SCV004018961.1

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

Description

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

#	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: Nov 10, 2024

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