NM_000535.7(PMS2):c.2008A>G (p.Lys670Glu) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 22, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000612857.5

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]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000731408	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Feb 20, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001363170	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Apr 22, 2019)	germline	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

SCV000731408

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Feb 20, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001363170

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Apr 22, 2019)

germline

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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731408.2

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

Description

The p.Lys670Glu variant in PMS2 has not been previously reported in individuals with Lynch syndrome or in large population studies. Computational prediction too ls and conservation analysis suggest that the p.Lys670Glu variant may impact the protein, though this information is not predictive enough to determine pathogen icity. In summary, the clinical significance of the p.Lys670Glu variant is uncer tain.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363170.1

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

Description

Variant summary: PMS2 c.2008A>G (p.Lys670Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 165648 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2008A>G, has been reported in the literature in individuals affected with breast cancer (Li_2018). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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

Last Updated: May 1, 2024

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