NM_024675.4(PALB2):c.2674G>A (p.Glu892Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Aug 3, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000131257.18

Allele description [Variation Report for NM_024675.4(PALB2):c.2674G>A (p.Glu892Lys)]

NM_024675.4(PALB2):c.2674G>A (p.Glu892Lys)

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.2674G>A (p.Glu892Lys)

HGVS:

NC_000016.10:g.23626310C>T
NG_007406.1:g.20048G>A
NM_024675.4:c.2674G>AMANE SELECT
NP_078951.2:p.Glu892Lys
NP_078951.2:p.Glu892Lys
LRG_308t1:c.2674G>A
LRG_308:g.20048G>A
LRG_308p1:p.Glu892Lys
NC_000016.9:g.23637631C>T
NM_024675.3:c.2674G>A
p.E892K

Protein change:

E892K

Links:

dbSNP: rs45476495

NCBI 1000 Genomes Browser:

rs45476495

Molecular consequence:

NM_024675.4:c.2674G>A - 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

Recent activity

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Rattus norvegicus myosin IF (Myo1f), mRNA
Rattus norvegicus myosin IF (Myo1f), mRNA
gi|1154067577|ref|NM_001108076.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186221	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Nov 12, 2020)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 17200668, 22241545, 25575445, 25980754, 26283626, 26534844, 28503720, 28779002, 29368341, 30287823 Citation Link,
SCV000685968	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 3, 2023)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 17200668, 22241545, 25186627, 25356972, 25980754, 26283626, 26689913, 28503720, 28779002, 29368341, 30287823, 30982232, 31214711, 32853339, 32980694, 33471991, 25741868
SCV002530716	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Sep 3, 2021)	germline	curation	PubMed (8) [See all records that cite these PMIDs] 25575445, 29368341, 17200668, 22241545, 25186627, 33471991, 32830346, 30287823 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186221

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Nov 12, 2020)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link,

SCV000685968

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 3, 2023)

germline

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

SCV002530716

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Sep 3, 2021)

germline

curation

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

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

Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families.

Li J, Meeks H, Feng BJ, Healey S, Thorne H, Makunin I, Ellis J; kConFab Investigators., Campbell I, Southey M, Mitchell G, Clouston D, Kirk J, Goldgar D, Chenevix-Trench G.

J Med Genet. 2016 Jan;53(1):34-42. doi: 10.1136/jmedgenet-2015-103452. Epub 2015 Nov 3.

PubMed [citation]

PMID:: 26534844
PMCID:: PMC4915734

BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.

Zhen DB, Rabe KG, Gallinger S, Syngal S, Schwartz AG, Goggins MG, Hruban RH, Cote ML, McWilliams RR, Roberts NJ, Cannon-Albright LA, Li D, Moyes K, Wenstrup RJ, Hartman AR, Seminara D, Klein AP, Petersen GM.

Genet Med. 2015 Jul;17(7):569-77. doi: 10.1038/gim.2014.153. Epub 2014 Nov 20.

PubMed [citation]

PMID:: 25356972
PMCID:: PMC4439391

See all PubMed Citations (20)

Details of each submission

From Ambry Genetics, SCV000186221.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000685968.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

This missense variant replaces glutamic acid with lysine at codon 892 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 17200668, 22241545, 25186627, 26283626, 28503720, 28779002, 33471991, 30982232), pancreatic cancer (PMID: 25356972), Lynch syndrome-associated cancer and colorectal polyps (PMID: 25980754), lung, stomach and prostate cancer (PMID: 26689913, 29368341, 32853339), and also detected in individuals unaffected with cancer (PMID: 28779002, 30287823, 32980694, 31214711, 33471991). In a breast cancer case-control meta-analysis, this variant was reported in 11/60455 cases and 9/53452 unaffected individuals with OR=1.081 (95%CI 0.448 to 2.608) (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010215). This variant has been identified in 20/282898 chromosomes 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

From Sema4, Sema4, SCV002530716.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (8)

#	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: Oct 13, 2024

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