NM_024675.4(PALB2):c.2246A>G (p.Glu749Gly) AND Familial cancer of breast

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 9, 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:: RCV003608216.2

Allele description [Variation Report for NM_024675.4(PALB2):c.2246A>G (p.Glu749Gly)]

NM_024675.4(PALB2):c.2246A>G (p.Glu749Gly)

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.2246A>G (p.Glu749Gly)

HGVS:

NC_000016.10:g.23629908T>C
NG_007406.1:g.16450A>G
NM_001407296.1:c.2186A>G
NM_001407297.1:c.2246A>G
NM_001407298.1:c.2246A>G
NM_001407299.1:c.2246A>G
NM_001407300.1:c.2246A>G
NM_001407301.1:c.2246A>G
NM_001407302.1:c.2246A>G
NM_001407304.1:c.1361A>G
NM_001407305.1:c.1361A>G
NM_001407306.1:c.1361A>G
NM_001407307.1:c.1361A>G
NM_001407308.1:c.1361A>G
NM_001407309.1:c.1361A>G
NM_001407310.1:c.1361A>G
NM_001407311.1:c.1361A>G
NM_001407312.1:c.458A>G
NM_001407313.1:c.458A>G
NM_001407314.1:c.49-633A>G
NM_024675.4:c.2246A>GMANE SELECT
NP_001394225.1:p.Glu729Gly
NP_001394226.1:p.Glu749Gly
NP_001394227.1:p.Glu749Gly
NP_001394228.1:p.Glu749Gly
NP_001394229.1:p.Glu749Gly
NP_001394230.1:p.Glu749Gly
NP_001394231.1:p.Glu749Gly
NP_001394233.1:p.Glu454Gly
NP_001394234.1:p.Glu454Gly
NP_001394235.1:p.Glu454Gly
NP_001394236.1:p.Glu454Gly
NP_001394237.1:p.Glu454Gly
NP_001394238.1:p.Glu454Gly
NP_001394239.1:p.Glu454Gly
NP_001394240.1:p.Glu454Gly
NP_001394241.1:p.Glu153Gly
NP_001394242.1:p.Glu153Gly
NP_078951.2:p.Glu749Gly
NP_078951.2:p.Glu749Gly
LRG_308t1:c.2246A>G
LRG_308:g.16450A>G
LRG_308p1:p.Glu749Gly
NC_000016.9:g.23641229T>C
NM_024675.3:c.2246A>G

Protein change:

E153G

Molecular consequence:

NM_001407314.1:c.49-633A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001407296.1:c.2186A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407297.1:c.2246A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407298.1:c.2246A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407299.1:c.2246A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407300.1:c.2246A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407301.1:c.2246A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407302.1:c.2246A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407304.1:c.1361A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407305.1:c.1361A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407306.1:c.1361A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407307.1:c.1361A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407308.1:c.1361A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407309.1:c.1361A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407310.1:c.1361A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407311.1:c.1361A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407312.1:c.458A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407313.1:c.458A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024675.4:c.2246A>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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E3 ubiquitin-protein ligase HECTD3 [Mus musculus]
E3 ubiquitin-protein ligase HECTD3 [Mus musculus]
gi|30424882|ref|NP_780453.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004504485	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 9, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004504485

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 9, 2023)

germline

clinical testing

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

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

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, SCV004504485.1

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

Description

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. 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 not expected to disrupt PALB2 protein function. This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 749 of the PALB2 protein (p.Glu749Gly).

#	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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