NM_000179.3(MSH6):c.3762A>T (p.Glu1254Asp) AND Lynch syndrome 5

Germline classification:: Conflicting interpretations of pathogenicity (2 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:: RCV000408995.4

Allele description [Variation Report for NM_000179.3(MSH6):c.3762A>T (p.Glu1254Asp)]

NM_000179.3(MSH6):c.3762A>T (p.Glu1254Asp)

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.3762A>T (p.Glu1254Asp)

Other names:

p.E1254D:GAA>GAT

HGVS:

NC_000002.12:g.47806319A>T
NG_007111.1:g.28173A>T
NG_008397.1:g.104357T>A
NM_000179.3:c.3762A>TMANE SELECT
NM_001281492.2:c.3372A>T
NM_001281493.2:c.2856A>T
NM_001281494.2:c.2856A>T
NP_000170.1:p.Glu1254Asp
NP_000170.1:p.Glu1254Asp
NP_001268421.1:p.Glu1124Asp
NP_001268422.1:p.Glu952Asp
NP_001268423.1:p.Glu952Asp
LRG_219t1:c.3762A>T
LRG_219:g.28173A>T
LRG_219p1:p.Glu1254Asp
NC_000002.11:g.48033458A>T
NM_000179.2:c.3762A>T
p.E1254D

Protein change:

E1124D

Links:

dbSNP: rs375459388

NCBI 1000 Genomes Browser:

rs375459388

Molecular consequence:

NM_000179.3:c.3762A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.3372A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.2856A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.2856A>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
SCV000487880	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Nov 24, 2015)	unknown	clinical testing	Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV004018969	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

SCV000487880

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Nov 24, 2015)

unknown

clinical testing

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV004018969

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

Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.

Pruss D, Morris B, Hughes E, Eggington JM, Esterling L, Robinson BS, van Kan A, Fernandes PH, Roa BB, Gutin A, Wenstrup RJ, Bowles KR.

Breast Cancer Res Treat. 2014 Aug;147(1):119-32. doi: 10.1007/s10549-014-3065-9. Epub 2014 Aug 2.

PubMed [citation]

PMID:: 25085752

Details of each submission

From Counsyl, SCV000487880.2

#	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., SCV004018969.1

#	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: Aug 25, 2024

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