NM_024675.4(PALB2):c.2810G>A (p.Gly937Glu) AND Familial cancer of breast

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 6, 2023
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:: RCV000206821.7

Allele description [Variation Report for NM_024675.4(PALB2):c.2810G>A (p.Gly937Glu)]

NM_024675.4(PALB2):c.2810G>A (p.Gly937Glu)

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.2810G>A (p.Gly937Glu)

HGVS:

NC_000016.10:g.23624033C>T
NG_007406.1:g.22325G>A
NM_024675.4:c.2810G>AMANE SELECT
NP_078951.2:p.Gly937Glu
NP_078951.2:p.Gly937Glu
LRG_308t1:c.2810G>A
LRG_308:g.22325G>A
LRG_308p1:p.Gly937Glu
NC_000016.9:g.23635354C>T
NM_024675.3:c.2810G>A
p.G937E

Protein change:

G937E

Links:

dbSNP: rs786202641

NCBI 1000 Genomes Browser:

rs786202641

Molecular consequence:

NM_024675.4:c.2810G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial
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
SCV000260184	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31636395, 28492532
SCV004202006	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 22, 2023)	unknown	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

SCV000260184

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 6, 2023)

germline

clinical testing

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

SCV004202006

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 22, 2023)

unknown

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	unknown	unknown	not provided	not provided	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

Functional characterization of 84 PALB2 variants of uncertain significance.

Wiltshire T, Ducy M, Foo TK, Hu C, Lee KY, Belur Nagaraj A, Rodrigue A, Gomes TT, Simard J, Monteiro ANA, Xia B, Carvalho MA, Masson JY, Couch FJ.

Genet Med. 2020 Mar;22(3):622-632. doi: 10.1038/s41436-019-0682-z. Epub 2019 Oct 21.

PubMed [citation]

PMID:: 31636395
PMCID:: PMC7056643

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000260184.6

#	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 glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 937 of the PALB2 protein (p.Gly937Glu). This variant is present in population databases (rs786202641, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 186029). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). 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.

#	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

From Baylor Genetics, SCV004202006.1

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

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

Last Updated: May 7, 2024

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