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NM_000535.7(PMS2):c.229G>A (p.Glu77Lys) AND Lynch syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 15, 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:
RCV003997851.2

Allele description [Variation Report for NM_000535.7(PMS2):c.229G>A (p.Glu77Lys)]

NM_000535.7(PMS2):c.229G>A (p.Glu77Lys)

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.229G>A (p.Glu77Lys)
HGVS:
  • NC_000007.14:g.6003993C>T
  • NG_008466.1:g.10114G>A
  • NM_000535.7:c.229G>AMANE SELECT
  • NM_001322003.2:c.-177G>A
  • NM_001322004.2:c.-177G>A
  • NM_001322005.2:c.-177G>A
  • NM_001322006.2:c.229G>A
  • NM_001322007.2:c.14G>A
  • NM_001322008.2:c.14G>A
  • NM_001322009.2:c.-177G>A
  • NM_001322010.2:c.-177G>A
  • NM_001322011.2:c.-656G>A
  • NM_001322012.2:c.-656G>A
  • NM_001322013.2:c.-177G>A
  • NM_001322014.2:c.229G>A
  • NM_001322015.2:c.-256G>A
  • NP_000526.2:p.Glu77Lys
  • NP_001308935.1:p.Glu77Lys
  • NP_001308936.1:p.Arg5Lys
  • NP_001308937.1:p.Arg5Lys
  • NP_001308943.1:p.Glu77Lys
  • LRG_161t1:c.229G>A
  • LRG_161:g.10114G>A
  • NC_000007.13:g.6043624C>T
  • NM_000535.5:c.229G>A
  • NR_136154.1:n.316G>A
Protein change:
E77K
Links:
dbSNP: rs751235177
NCBI 1000 Genomes Browser:
rs751235177
Molecular consequence:
  • NM_001322003.2:c.-177G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322004.2:c.-177G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322005.2:c.-177G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322009.2:c.-177G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322010.2:c.-177G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322011.2:c.-656G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322012.2:c.-656G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322013.2:c.-177G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001322015.2:c.-256G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000535.7:c.229G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322006.2:c.229G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322007.2:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322008.2:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001322014.2:c.229G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136154.1:n.316G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
4

Condition(s)

Name:
Lynch syndrome
Identifiers:
MONDO: MONDO:0005835; MedGen: C4552100

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004842144All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Aug 15, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown4not providednot provided108544not providedclinical testing

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004842144.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testing PubMed (2)

Description

This missense variant replaces glutamic acid with lysine at codon 77 of the PMS2 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 reported for this variant. In a large breast cancer case-control study, this variant has been reported in 5/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/250862 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided4not providednot providednot provided

Last Updated: Sep 29, 2024