NM_000179.3(MSH6):c.59C>T (p.Ala20Val) 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:: RCV000412384.9

Allele description [Variation Report for NM_000179.3(MSH6):c.59C>T (p.Ala20Val)]

NM_000179.3(MSH6):c.59C>T (p.Ala20Val)

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.59C>T (p.Ala20Val)

Other names:

p.A20V:GCC>GTC

HGVS:

NC_000002.12:g.47783292C>T
NG_007111.1:g.5146C>T
NM_000179.3:c.59C>TMANE SELECT
NM_001281492.2:c.59C>T
NM_001281493.2:c.-678C>T
NP_000170.1:p.Ala20Val
NP_000170.1:p.Ala20Val
NP_001268421.1:p.Ala20Val
LRG_219t1:c.59C>T
LRG_219:g.5146C>T
LRG_219p1:p.Ala20Val
NC_000002.11:g.48010431C>T
NM_000179.2:c.59C>T
P52701:p.Ala20Val
p.A20V

Protein change:

A20V

Links:

UniProtKB: P52701#VAR_043943; dbSNP: rs63750664

NCBI 1000 Genomes Browser:

rs63750664

Molecular consequence:

NM_001281493.2:c.-678C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000179.3:c.59C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.59C>T - 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
SCV000487828	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Nov 24, 2015)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11153917, 18566915, 22102614 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV001299751	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22290698, 22102614, 18566915, 11153917 Citation Link,
SCV004018951	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	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

SCV000487828

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Nov 24, 2015)

unknown

clinical testing

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

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV001299751

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

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

Citation Link,

SCV004018951

Myriad Genetics, Inc.

criteria provided, single submitter

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

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	germline	unknown	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

Classification of mismatch repair gene missense variants with PON-MMR.

Ali H, Olatubosun A, Vihinen M.

Hum Mutat. 2012 Apr;33(4):642-50. doi: 10.1002/humu.22038.

PubMed [citation]

PMID:: 22290698

A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants.

Drost M, Zonneveld JB, van Hees S, Rasmussen LJ, Hofstra RM, de Wind N.

Hum Mutat. 2012 Mar;33(3):488-94. doi: 10.1002/humu.22000. Epub 2011 Dec 29.

PubMed [citation]

PMID:: 22102614

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000487828.2

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

#	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 Illumina Laboratory Services, Illumina, SCV001299751.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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

From Myriad Genetics, Inc., SCV004018951.1

#	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 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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.

#	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: May 7, 2024

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