NM_024675.4(PALB2):c.2831T>A (p.Ile944Asn) AND Familial cancer of breast

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 5, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV003162715.2

Allele description [Variation Report for NM_024675.4(PALB2):c.2831T>A (p.Ile944Asn)]

NM_024675.4(PALB2):c.2831T>A (p.Ile944Asn)

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.2831T>A (p.Ile944Asn)

Other names:

NM_024675.3(PALB2):c.2831T>A; p.Ile944Asn

HGVS:

NC_000016.10:g.23624012A>T
NG_007406.1:g.22346T>A
NM_024675.4:c.2831T>AMANE SELECT
NP_078951.2:p.Ile944Asn
NP_078951.2:p.Ile944Asn
LRG_308t1:c.2831T>A
LRG_308:g.22346T>A
LRG_308p1:p.Ile944Asn
NC_000016.9:g.23635333A>T
NC_000016.9:g.23635333A>T
NM_024675.3:c.2831T>A
p.I944N

Protein change:

I944N

Links:

dbSNP: rs201817103

NCBI 1000 Genomes Browser:

rs201817103

Molecular consequence:

NM_024675.4:c.2831T>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
SCV003915562	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen HBOP VCEP ACMG Specifications PALB2 V1.0.0)	Uncertain significance (Apr 5, 2023)	germline	curation	Citation Link,
SCV004632425	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 20, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31636395, 31757951, 30638972, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003915562

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen HBOP VCEP ACMG Specifications PALB2 V1.0.0)

Uncertain significance
(Apr 5, 2023)

germline

curation

Citation Link,

SCV004632425

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 20, 2022)

germline

clinical testing

PubMed (4)
[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, curation

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

Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2.

Boonen RACM, Rodrigue A, Stoepker C, Wiegant WW, Vroling B, Sharma M, Rother MB, Celosse N, Vreeswijk MPG, Couch F, Simard J, Devilee P, Masson JY, van Attikum H.

Nat Commun. 2019 Nov 22;10(1):5296. doi: 10.1038/s41467-019-13194-2.

PubMed [citation]

PMID:: 31757951
PMCID:: PMC6876638

See all PubMed Citations (4)

Details of each submission

From ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen, SCV003915562.1

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

Description

The c.2831T>A variant in PALB2 is a missense variant predicted to cause substitution of isoleucine by asparagine at amino acid 944 (p.Ile944Asn). This variant is absent from gnomAD v2.1.1. This variant is non-functional in multiple different protein assays (PMID: 31757951, 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM2_Supporting, BP1)

#	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 Invitae, SCV004632425.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is not present in population databases (gnomAD no frequency). 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: 31636395, 31757951). 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. ClinVar contains an entry for this variant (Variation ID: 187262). This missense change has been observed in individual(s) with breast cancer (PMID: 30638972). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 944 of the PALB2 protein (p.Ile944Asn).

#	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: May 1, 2024

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