NM_000179.3(MSH6):c.2281A>G (p.Arg761Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 19, 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:: RCV000129031.17

Allele description [Variation Report for NM_000179.3(MSH6):c.2281A>G (p.Arg761Gly)]

NM_000179.3(MSH6):c.2281A>G (p.Arg761Gly)

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.2281A>G (p.Arg761Gly)

HGVS:

NC_000002.12:g.47800264A>G
NG_007111.1:g.22118A>G
NM_000179.3:c.2281A>GMANE SELECT
NM_001281492.2:c.1891A>G
NM_001281493.2:c.1375A>G
NM_001281494.2:c.1375A>G
NP_000170.1:p.Arg761Gly
NP_000170.1:p.Arg761Gly
NP_001268421.1:p.Arg631Gly
NP_001268422.1:p.Arg459Gly
NP_001268423.1:p.Arg459Gly
LRG_219t1:c.2281A>G
LRG_219:g.22118A>G
LRG_219p1:p.Arg761Gly
NC_000002.11:g.48027403A>G
NM_000179.2:c.2281A>G
p.R761G

Protein change:

R459G

Links:

dbSNP: rs199876321

NCBI 1000 Genomes Browser:

rs199876321

Molecular consequence:

NM_000179.3:c.2281A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281492.2:c.1891A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281493.2:c.1375A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281494.2:c.1375A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

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Rutidea decorticata voucher Maurin 14 (K) trnT-trnL intergenic spacer, partial s...
Rutidea decorticata voucher Maurin 14 (K) trnT-trnL intergenic spacer, partial sequence; tRNA-Leu (trnL) gene and trnL-trnF intergenic spacer, complete sequence; and tRNA-Phe (trnF) gene, partial sequence; chloroplast
gi|742522756|gb|KM592148.1|

Nucleotide
Coptosperma mitochondrioides voucher Bremer et al. 5127 (S) trnT-trnL intergenic...
Coptosperma mitochondrioides voucher Bremer et al. 5127 (S) trnT-trnL intergenic spacer, partial sequence; tRNA-Leu (trnL-UAA) gene and trnL-trnF intergenic spacer, complete sequence; and tRNA-Phe (trnF) gene, partial sequence; chloroplast
gi|817361829|gb|KJ815597.1|

Nucleotide
Tarenna bipindensis voucher Jongkind 8495 (BR) trnT-trnL intergenic spacer, part...
Tarenna bipindensis voucher Jongkind 8495 (BR) trnT-trnL intergenic spacer, partial sequence; tRNA-Leu (trnL) gene and trnL-trnF intergenic spacer, complete sequence; and tRNA-Phe (trnF) gene, partial sequence; chloroplast
gi|742522769|gb|KM592161.1|

Nucleotide
Gardenia rutenbergiana voucher Groeninckx & al 24 (BR) ribosomal protein S16 (rp...
Gardenia rutenbergiana voucher Groeninckx & al 24 (BR) ribosomal protein S16 (rps16) gene, intron; chloroplast
gi|742522812|gb|KM592204.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172939	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Apr 6, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 28502729, 28640387, 29684080, 30256826, 33471991 Citation Link,
SCV000685275	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 19, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 28502729, 28640387, 29684080, 30256826, 33471991, 35245693, 25741868
SCV002535716	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jul 21, 2021)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 30256826, 28502729, 28640387, 29684080 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000172939

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Apr 6, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000685275

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 19, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002535716

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jul 21, 2021)

germline

curation

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

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, curation

Citations

PubMed

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance.

Castillo-Guardiola V, Rosado-Jiménez L, Sarabia-Meseguer MD, Marín-Vera M, Macías-Cerrolaza JA, García-Hernández R, Zafra-Poves M, Sánchez-Henarejos P, Moreno-Locubiche MÁ, Cuevas-Tortosa E, Arnaldos-Carrillo M, Ayala de la Peña F, Alonso-Romero JL, Noguera-Velasco JA, Ruiz-Espejo F.

Eur J Med Genet. 2022 Apr;65(4):104468. doi: 10.1016/j.ejmg.2022.104468. Epub 2022 Mar 1.

PubMed [citation]

PMID:: 35245693

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000172939.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000685275.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces arginine with glycine at codon 761 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals with personal and/or family history of Lynch syndrome-associated cancer and/or polyps (PMID: 28502729, 30256826), colorectal cancer who also had a pathogenic MUTYH variant (PMID: 28640387), skin melanoma (PMID: 29684080), breast cancer (PMID: 35245693), or lymphoblastic leukemia (DOI: 10.5603/oJ.2021.0046). In a large breast cancer case-control study, this variant was reported in 7/60466 cases and 7/53461 unaffected controls (PMID: 33471991). This variant has been identified in 15/251138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain 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 Sema4, Sema4, SCV002535716.1

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

#	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

Last Updated: Oct 8, 2024

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