NM_024675.4(PALB2):c.3054G>C (p.Glu1018Asp) AND Familial cancer of breast

Germline classification:: Benign (5 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:: RCV000114588.32

Allele description [Variation Report for NM_024675.4(PALB2):c.3054G>C (p.Glu1018Asp)]

NM_024675.4(PALB2):c.3054G>C (p.Glu1018Asp)

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.3054G>C (p.Glu1018Asp)

Other names:

p.E1018D:GAG>GAC; NM_024675.3(PALB2):c.3054G>C; p.Glu1018Asp

HGVS:

NC_000016.10:g.23621421C>G
NG_007406.1:g.24937G>C
NM_024675.4:c.3054G>CMANE SELECT
NP_078951.2:p.Glu1018Asp
NP_078951.2:p.Glu1018Asp
LRG_308t1:c.3054G>C
LRG_308:g.24937G>C
LRG_308p1:p.Glu1018Asp
NC_000016.9:g.23632742C>G
NM_024675.3:c.3054G>C
p.E1018D

Protein change:

E1018D

Links:

dbSNP: rs183489969

NCBI 1000 Genomes Browser:

rs183489969

Molecular consequence:

NM_024675.4:c.3054G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000253601	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Jan 30, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000268021	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	criteria provided, single submitter (Thompson et al. (Breast Cancer Res. 2015))	Uncertain significance (Jun 1, 2015)	germline	case-control	PubMed (1) [See all records that cite this PMID]
SCV001193337	Leiden Open Variation Database	no assertion criteria provided	Likely benign (May 13, 2019)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 22241545, 23977390, 30287823
SCV003915563	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)	Benign (Apr 5, 2023)	germline	curation	Citation Link,
SCV004175576	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Apr 16, 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	yes	1	not provided	not provided	1996	not provided	clinical testing, case-control
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	no	1	not provided	not provided	1998	not provided	curation, case-control

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

Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.

Thompson ER, Gorringe KL, Rowley SM, Wong-Brown MW, McInerny S, Li N, Trainer AH, Devereux L, Doyle MA, Li J, Lupat R, Delatycki MB; LifePool Investigators., Mitchell G, James PA, Scott RJ, Campbell IG.

Breast Cancer Res. 2015 Aug 19;17:111. doi: 10.1186/s13058-015-0627-7.

PubMed [citation]

PMID:: 26283626
PMCID:: PMC4539664

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000253601.12

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, SCV000268021.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	case-control	PubMed (1)
2	not provided	1	not provided	not provided	case-control	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1996	not provided	not provided		1	not provided	not provided	not provided
2	germline	no	1998	not provided	not provided		1	not provided	not provided	not provided

From Leiden Open Variation Database, SCV001193337.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen, SCV003915563.1

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

Description

The c.3054G>C variant in PALB2 is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 1018 (p.Glu1018Asp). The filtering allele frequency in gnomAD v2.1.1 is 0.004 in the East Asian population, which is higher than the ClinGen HBOP threshold (>0.001) for BA1, and therefore meets this criterion. This variant has been observed in a homozygous state and phase unknown with numerous other PALB2 variants that are tentatively classified as likely pathogenic or pathogenic by the HBOP VCEP in individuals without Fanconi Anemia (GeneDx, Ambry Genetics, Invitae). This variant is functional in multiple different protein assays (PMID 31757951); 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 the criteria to be classified as benign 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. (BA1, BP2_Moderate, 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 Genetics and Molecular Pathology, SA Pathology, SCV004175576.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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