NM_000179.3(MSH6):c.905G>C (p.Arg302Thr) 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:: RCV000662957.4

Allele description [Variation Report for NM_000179.3(MSH6):c.905G>C (p.Arg302Thr)]

NM_000179.3(MSH6):c.905G>C (p.Arg302Thr)

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.905G>C (p.Arg302Thr)

HGVS:

NC_000002.12:g.47798888G>C
NG_007111.1:g.20742G>C
NM_000179.3:c.905G>CMANE SELECT
NM_001281492.2:c.515G>C
NM_001281493.2:c.-2G>C
NM_001281494.2:c.-2G>C
NM_001406795.1:c.1001G>C
NM_001406796.1:c.905G>C
NM_001406797.1:c.608G>C
NM_001406798.1:c.905G>C
NM_001406799.1:c.380G>C
NM_001406800.1:c.905G>C
NM_001406801.1:c.608G>C
NM_001406802.1:c.1001G>C
NM_001406803.1:c.905G>C
NM_001406804.1:c.827G>C
NM_001406805.1:c.608G>C
NM_001406806.1:c.380G>C
NM_001406807.1:c.380G>C
NM_001406808.1:c.905G>C
NM_001406809.1:c.905G>C
NM_001406811.1:c.-2G>C
NM_001406812.1:c.-2G>C
NM_001406813.1:c.911G>C
NM_001406814.1:c.-2G>C
NM_001406815.1:c.-2G>C
NM_001406816.1:c.-2G>C
NM_001406817.1:c.905G>C
NM_001406818.1:c.608G>C
NM_001406819.1:c.608G>C
NM_001406820.1:c.608G>C
NM_001406821.1:c.608G>C
NM_001406822.1:c.608G>C
NM_001406823.1:c.-2G>C
NM_001406824.1:c.608G>C
NM_001406825.1:c.608G>C
NM_001406826.1:c.737G>C
NM_001406827.1:c.608G>C
NM_001406828.1:c.608G>C
NM_001406829.1:c.-2G>C
NM_001406830.1:c.608G>C
NM_001407362.1:c.628-1778G>C
NP_000170.1:p.Arg302Thr
NP_000170.1:p.Arg302Thr
NP_001268421.1:p.Arg172Thr
NP_001393724.1:p.Arg334Thr
NP_001393725.1:p.Arg302Thr
NP_001393726.1:p.Arg203Thr
NP_001393727.1:p.Arg302Thr
NP_001393728.1:p.Arg127Thr
NP_001393729.1:p.Arg302Thr
NP_001393730.1:p.Arg203Thr
NP_001393731.1:p.Arg334Thr
NP_001393732.1:p.Arg302Thr
NP_001393733.1:p.Arg276Thr
NP_001393734.1:p.Arg203Thr
NP_001393735.1:p.Arg127Thr
NP_001393736.1:p.Arg127Thr
NP_001393737.1:p.Arg302Thr
NP_001393738.1:p.Arg302Thr
NP_001393742.1:p.Arg304Thr
NP_001393746.1:p.Arg302Thr
NP_001393747.1:p.Arg203Thr
NP_001393748.1:p.Arg203Thr
NP_001393749.1:p.Arg203Thr
NP_001393750.1:p.Arg203Thr
NP_001393751.1:p.Arg203Thr
NP_001393753.1:p.Arg203Thr
NP_001393754.1:p.Arg203Thr
NP_001393755.1:p.Arg246Thr
NP_001393756.1:p.Arg203Thr
NP_001393757.1:p.Arg203Thr
NP_001393759.1:p.Arg203Thr
LRG_219t1:c.905G>C
LRG_219:g.20742G>C
LRG_219p1:p.Arg302Thr
NC_000002.11:g.48026027G>C
NM_000179.2:c.905G>C
NR_176257.1:n.994G>C
NR_176258.1:n.994G>C
NR_176259.1:n.994G>C
NR_176261.1:n.994G>C
p.R302T

Protein change:

R127T

Links:

dbSNP: rs587781510

NCBI 1000 Genomes Browser:

rs587781510

Molecular consequence:

NM_001281493.2:c.-2G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281494.2:c.-2G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406811.1:c.-2G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406812.1:c.-2G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406814.1:c.-2G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406815.1:c.-2G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406816.1:c.-2G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406823.1:c.-2G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001406829.1:c.-2G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407362.1:c.628-1778G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000179.3:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.515G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406795.1:c.1001G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406796.1:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406797.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406798.1:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406799.1:c.380G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406800.1:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406801.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406802.1:c.1001G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406803.1:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406804.1:c.827G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406805.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406806.1:c.380G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406807.1:c.380G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406808.1:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406809.1:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406813.1:c.911G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406817.1:c.905G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406818.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406819.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406820.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406821.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406822.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406824.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406825.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406826.1:c.737G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406827.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406828.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406830.1:c.608G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_176257.1:n.994G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176258.1:n.994G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176259.1:n.994G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176261.1:n.994G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000785927	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Jan 15, 2018)	unknown	clinical testing	Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV001135798	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV004019003	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

SCV000785927

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Jan 15, 2018)

unknown

clinical testing

Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf,

Citation Link,

SCV001135798

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV004019003

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, SCV000785927.2

#	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 Mendelics, SCV001135798.1

#	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., SCV004019003.1

#	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: May 1, 2024

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