NM_024675.4(PALB2):c.3073G>A (p.Ala1025Thr) AND Familial cancer of breast

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 29, 2024
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:: RCV000202108.13

Allele description [Variation Report for NM_024675.4(PALB2):c.3073G>A (p.Ala1025Thr)]

NM_024675.4(PALB2):c.3073G>A (p.Ala1025Thr)

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.3073G>A (p.Ala1025Thr)

HGVS:

NC_000016.10:g.23621402C>T
NG_007406.1:g.24956G>A
NM_024675.4:c.3073G>AMANE SELECT
NP_078951.2:p.Ala1025Thr
NP_078951.2:p.Ala1025Thr
LRG_308t1:c.3073G>A
LRG_308:g.24956G>A
LRG_308p1:p.Ala1025Thr
NC_000016.9:g.23632723C>T
NM_024675.3:c.3073G>A
Q86YC2:p.Ala1025Thr

Protein change:

A1025T

Links:

UniProtKB: Q86YC2#VAR_066378; dbSNP: rs746872839

NCBI 1000 Genomes Browser:

rs746872839

Molecular consequence:

NM_024675.4:c.3073G>A - 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
SCV000256601	Centro Diagnostico Italiano	no assertion criteria provided	Uncertain significance (Apr 21, 2015)	unknown	research
SCV000290863	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21618343, 27978560, 31586400, 31636395, 33964450, 28492532
SCV005055045	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 16, 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

SCV000256601

Centro Diagnostico Italiano

no assertion criteria provided

Uncertain significance
(Apr 21, 2015)

unknown

research

SCV000290863

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 29, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV005055045

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 16, 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
	unknown	yes	1	not provided	not provided	not provided	not provided	research
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

Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer.

Hellebrand H, Sutter C, Honisch E, Gross E, Wappenschmidt B, Schem C, Deissler H, Ditsch N, Gress V, Kiechle M, Bartram CR, Schmutzler RK, Niederacher D, Arnold N, Meindl A.

Hum Mutat. 2011 Jun;32(6):E2176-88. doi: 10.1002/humu.21478. Epub 2011 Feb 24.

PubMed [citation]

PMID:: 21618343

Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.

Pearlman R, Frankel WL, Swanson B, Zhao W, Yilmaz A, Miller K, Bacher J, Bigley C, Nelsen L, Goodfellow PJ, Goldberg RM, Paskett E, Shields PG, Freudenheim JL, Stanich PP, Lattimer I, Arnold M, Liyanarachchi S, Kalady M, Heald B, Greenwood C, Paquette I, et al.

JAMA Oncol. 2017 Apr 1;3(4):464-471. doi: 10.1001/jamaoncol.2016.5194.

PubMed [citation]

PMID:: 27978560
PMCID:: PMC5564179

See all PubMed Citations (7)

Details of each submission

From Centro Diagnostico Italiano, SCV000256601.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	research	not provided

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000290863.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1025 of the PALB2 protein (p.Ala1025Thr). This variant is present in population databases (rs746872839, gnomAD 0.003%). This missense change has been observed in individual(s) with breast or colon cancer (PMID: 21618343, 27978560). ClinVar contains an entry for this variant (Variation ID: 217917). 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: 31586400, 31636395, 33964450). 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, SCV005055045.1

#	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: Oct 8, 2024

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