NM_024675.4(PALB2):c.3080T>G (p.Leu1027Arg) AND Familial cancer of breast

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 22, 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:: RCV003501930.2

Allele description [Variation Report for NM_024675.4(PALB2):c.3080T>G (p.Leu1027Arg)]

NM_024675.4(PALB2):c.3080T>G (p.Leu1027Arg)

Gene:

PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.3080T>G (p.Leu1027Arg)

HGVS:

NC_000016.10:g.23621395A>C
NG_007406.1:g.24963T>G
NM_001407296.1:c.3020T>G
NM_001407297.1:c.3008T>G
NM_001407298.1:c.2918T>G
NM_001407299.1:c.3080T>G
NM_001407300.1:c.2834+2614T>G
NM_001407301.1:c.3080T>G
NM_001407302.1:c.2918T>G
NM_001407304.1:c.2195T>G
NM_001407305.1:c.2195T>G
NM_001407306.1:c.2195T>G
NM_001407307.1:c.2033T>G
NM_001407308.1:c.2195T>G
NM_001407309.1:c.2195T>G
NM_001407310.1:c.2195T>G
NM_001407311.1:c.2195T>G
NM_001407312.1:c.1292T>G
NM_001407313.1:c.1292T>G
NM_001407314.1:c.614T>G
NM_024675.4:c.3080T>GMANE SELECT
NP_001394225.1:p.Leu1007Arg
NP_001394226.1:p.Leu1003Arg
NP_001394227.1:p.Leu973Arg
NP_001394228.1:p.Leu1027Arg
NP_001394230.1:p.Leu1027Arg
NP_001394231.1:p.Leu973Arg
NP_001394233.1:p.Leu732Arg
NP_001394234.1:p.Leu732Arg
NP_001394235.1:p.Leu732Arg
NP_001394236.1:p.Leu678Arg
NP_001394237.1:p.Leu732Arg
NP_001394238.1:p.Leu732Arg
NP_001394239.1:p.Leu732Arg
NP_001394240.1:p.Leu732Arg
NP_001394241.1:p.Leu431Arg
NP_001394242.1:p.Leu431Arg
NP_001394243.1:p.Leu205Arg
NP_078951.2:p.Leu1027Arg
NP_078951.2:p.Leu1027Arg
LRG_308t1:c.3080T>G
LRG_308:g.24963T>G
LRG_308p1:p.Leu1027Arg
NC_000016.9:g.23632716A>C
NM_024675.3:c.3080T>G

Protein change:

L1003R

Molecular consequence:

NM_001407300.1:c.2834+2614T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001407296.1:c.3020T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407297.1:c.3008T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407298.1:c.2918T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407299.1:c.3080T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407301.1:c.3080T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407302.1:c.2918T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407304.1:c.2195T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407305.1:c.2195T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407306.1:c.2195T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407307.1:c.2033T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407308.1:c.2195T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407309.1:c.2195T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407310.1:c.2195T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407311.1:c.2195T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407312.1:c.1292T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407313.1:c.1292T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407314.1:c.614T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024675.4:c.3080T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004306500	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33811135, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004306500

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 22, 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

Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore.

Ng PS, Boonen RA, Wijaya E, Chong CE, Sharma M, Knaup S, Mariapun S, Ho WK, Lim J, Yoon SY, Mohd Taib NA, See MH, Li J, Lim SH, Tan EY, Tan BK, Tan SM, Tan VK, van Dam RM, Rahmat K, Yip CH, Carvalho S, et al.

J Med Genet. 2022 May;59(5):481-491. doi: 10.1136/jmedgenet-2020-107471. Epub 2021 Apr 2.

PubMed [citation]

PMID:: 33811135
PMCID:: PMC9046754

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, SCV004306500.1

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1027 of the PALB2 protein (p.Leu1027Arg). 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. Experimental studies have shown that this missense change affects PALB2 function (PMID: 33811135). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function. This missense change has been observed in individual(s) with breast cancer (PMID: 33811135). This variant is not present in population databases (gnomAD no frequency).

#	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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