NM_000535.7(PMS2):c.2008A>G (p.Lys670Glu) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 23, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001214793.8

Allele description [Variation Report for NM_000535.7(PMS2):c.2008A>G (p.Lys670Glu)]

NM_000535.7(PMS2):c.2008A>G (p.Lys670Glu)

Gene:

PMS2:PMS1 homolog 2, mismatch repair system component [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_000535.7(PMS2):c.2008A>G (p.Lys670Glu)

HGVS:

NC_000007.14:g.5982990T>C
NG_008466.1:g.31117A>G
NM_000535.7:c.2008A>GMANE SELECT
NM_001322003.2:c.1603A>G
NM_001322004.2:c.1603A>G
NM_001322005.2:c.1603A>G
NM_001322006.2:c.1852A>G
NM_001322007.2:c.1690A>G
NM_001322008.2:c.1690A>G
NM_001322009.2:c.1603A>G
NM_001322010.2:c.1447A>G
NM_001322011.2:c.1075A>G
NM_001322012.2:c.1075A>G
NM_001322013.2:c.1435A>G
NM_001322014.2:c.2008A>G
NM_001322015.2:c.1699A>G
NP_000526.2:p.Lys670Glu
NP_001308932.1:p.Lys535Glu
NP_001308933.1:p.Lys535Glu
NP_001308934.1:p.Lys535Glu
NP_001308935.1:p.Lys618Glu
NP_001308936.1:p.Lys564Glu
NP_001308937.1:p.Lys564Glu
NP_001308938.1:p.Lys535Glu
NP_001308939.1:p.Lys483Glu
NP_001308940.1:p.Lys359Glu
NP_001308941.1:p.Lys359Glu
NP_001308942.1:p.Lys479Glu
NP_001308943.1:p.Lys670Glu
NP_001308944.1:p.Lys567Glu
LRG_161t1:c.2008A>G
LRG_161:g.31117A>G
NC_000007.13:g.6022621T>C
NM_000535.5:c.2008A>G
NM_000535.6:c.2008A>G
NR_136154.1:n.2095A>G

Protein change:

K359E

Links:

dbSNP: rs1554295980

NCBI 1000 Genomes Browser:

rs1554295980

Molecular consequence:

NM_000535.7:c.2008A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322003.2:c.1603A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322004.2:c.1603A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322005.2:c.1603A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322006.2:c.1852A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322007.2:c.1690A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322008.2:c.1690A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322009.2:c.1603A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322010.2:c.1447A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322011.2:c.1075A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322012.2:c.1075A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322013.2:c.1435A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322014.2:c.2008A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322015.2:c.1699A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136154.1:n.2095A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001386497	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29752822, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001386497

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 23, 2023)

germline

clinical testing

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

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

Citations

PubMed

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.

Li JY, Jing R, Wei H, Wang M, Xiaowei Q, Liu H, Jian L, Ou JH, Jiang WH, Tian FG, Sheng Y, Li HY, Xu H, Zhang RS, Guan AH, Liu K, Jiang HC, Ren Y, He JJ, Huang W, Liao N, Cai X, et al.

Int J Cancer. 2019 Jan 15;144(2):281-289. doi: 10.1002/ijc.31601. Epub 2018 Nov 8.

PubMed [citation]

PMID:: 29752822

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001386497.5

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

Description

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 517233). This missense change has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer (PMID: 29752822). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 670 of the PMS2 protein (p.Lys670Glu).

#	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: Sep 29, 2024

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