NM_024675.4(PALB2):c.3331C>G (p.Pro1111Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 24, 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:: RCV000222857.12

Allele description [Variation Report for NM_024675.4(PALB2):c.3331C>G (p.Pro1111Ala)]

NM_024675.4(PALB2):c.3331C>G (p.Pro1111Ala)

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.3331C>G (p.Pro1111Ala)

HGVS:

NC_000016.10:g.23607883G>C
NG_007406.1:g.38475C>G
NM_024675.4:c.3331C>GMANE SELECT
NP_078951.2:p.Pro1111Ala
NP_078951.2:p.Pro1111Ala
LRG_308t1:c.3331C>G
LRG_308:g.38475C>G
LRG_308p1:p.Pro1111Ala
NC_000016.9:g.23619204G>C
NM_024675.3:c.3331C>G

Protein change:

P1111A

Links:

dbSNP: rs864622193

NCBI 1000 Genomes Browser:

rs864622193

Molecular consequence:

NM_024675.4:c.3331C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000273214	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29522266, 31757951 Citation Link,
SCV000686031	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 8, 2020)	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

SCV000273214

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 24, 2023)

germline

clinical testing

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

Citation Link,

SCV000686031

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 8, 2020)

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

Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer.

Hauke J, Horvath J, Groß E, Gehrig A, Honisch E, Hackmann K, Schmidt G, Arnold N, Faust U, Sutter C, Hentschel J, Wang-Gohrke S, Smogavec M, Weber BHF, Weber-Lassalle N, Weber-Lassalle K, Borde J, Ernst C, Altmüller J, Volk AE, Thiele H, Hübbel V, et al.

Cancer Med. 2018 Apr;7(4):1349-1358. doi: 10.1002/cam4.1376. Epub 2018 Mar 9.

PubMed [citation]

PMID:: 29522266
PMCID:: PMC5911592

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 (3)

Details of each submission

From Ambry Genetics, SCV000273214.8

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

Description

The p.P1111A variant (also known as c.3331C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide position 3331. The proline at codon 1111 is replaced by alanine, an amino acid with highly similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358). In one functional study, this variant did not significantly impair homologous recombination efficiency compared to wild-type, and was classified as a variant of uncertain significance by the authors (Boonen RACM et al. Nat Commun. 2019 11;10:5296). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000686031.4

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

Description

This missense variant replaces proline with alanine at codon 1111 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant resulted in normal repair activity in mouse cells (PMID: 31757951). To our knowledge, this variant has been reported in an individual affected with breast cancer (PMID: 29522266). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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

Last Updated: May 1, 2024

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