NM_024675.4(PALB2):c.2748+1G>C AND Familial cancer of breast

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 28, 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:: RCV000409294.8

Allele description [Variation Report for NM_024675.4(PALB2):c.2748+1G>C]

NM_024675.4(PALB2):c.2748+1G>C

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.2748+1G>C

HGVS:

NC_000016.10:g.23626235C>G
NG_007406.1:g.20123G>C
NM_001407296.1:c.2688+1G>C
NM_001407297.1:c.2676+1G>C
NM_001407298.1:c.2587-2141G>C
NM_001407299.1:c.2748+1G>C
NM_001407300.1:c.2748+1G>C
NM_001407301.1:c.2748+1G>C
NM_001407302.1:c.2587-2141G>C
NM_001407304.1:c.1863+1G>C
NM_001407305.1:c.1863+1G>C
NM_001407306.1:c.1863+1G>C
NM_001407307.1:c.1702-2141G>C
NM_001407308.1:c.1863+1G>C
NM_001407309.1:c.1863+1G>C
NM_001407310.1:c.1863+1G>C
NM_001407311.1:c.1863+1G>C
NM_001407312.1:c.960+1G>C
NM_001407313.1:c.960+1G>C
NM_001407314.1:c.282+1G>C
NM_024675.4:c.2748+1G>CMANE SELECT
LRG_308t1:c.2748+1G>C
LRG_308:g.20123G>C
NC_000016.9:g.23637556C>G
NM_024675.3:c.2748+1G>C

Links:

dbSNP: rs753153576

NCBI 1000 Genomes Browser:

rs753153576

Molecular consequence:

NM_001407298.1:c.2587-2141G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001407302.1:c.2587-2141G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001407307.1:c.1702-2141G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001407296.1:c.2688+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407297.1:c.2676+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407299.1:c.2748+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407300.1:c.2748+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407301.1:c.2748+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407304.1:c.1863+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407305.1:c.1863+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407306.1:c.1863+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407308.1:c.1863+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407309.1:c.1863+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407310.1:c.1863+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407311.1:c.1863+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407312.1:c.960+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407313.1:c.960+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407314.1:c.282+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_024675.4:c.2748+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000489669	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Nov 2, 2016)	unknown	clinical testing	Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV002312773	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 28, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 28825143, 30720863, 31263054, 31841383, 30890586, 28492532
SCV003936140	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 5, 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

SCV000489669

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Likely pathogenic
(Nov 2, 2016)

unknown

clinical testing

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV002312773

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 28, 2023)

germline

clinical testing

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

SCV003936140

KCCC/NGS Laboratory, Kuwait Cancer Control Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 5, 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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer.

Zhang K, Zhou J, Zhu X, Luo M, Xu C, Yu J, Deng M, Zheng S, Chen Y.

Breast Cancer Res Treat. 2017 Dec;166(3):865-873. doi: 10.1007/s10549-017-4425-z. Epub 2017 Aug 20.

PubMed [citation]

PMID:: 28825143

Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China.

Deng M, Chen HH, Zhu X, Luo M, Zhang K, Xu CJ, Hu KM, Cheng P, Zhou JJ, Zheng S, Chen YD.

Int J Cancer. 2019 Sep 15;145(6):1517-1528. doi: 10.1002/ijc.32184. Epub 2019 Feb 22.

PubMed [citation]

PMID:: 30720863

See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000489669.2

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

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002312773.3

#	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 affects a donor splice site in intron 7 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 28825143, 30720863, 31263054, 31841383). ClinVar contains an entry for this variant (Variation ID: 372056). Studies have shown that disruption of this splice site results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 30890586). Other variant(s) that result in loss of exon 7 have been determined to be pathogenic (Invitae). This suggests that this variant may also be clinically significant and likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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 KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV003936140.1

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

Description

This sequence change affects a donor splice site in intron 7 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 28825143, 30720863, 31263054, 31841383). ClinVar contains an entry for this variant (Variation ID: 372056). Studies have shown that disruption of this splice site results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 30890586). This variant disrupts the WD40-like repeats of the PALB2 protein, which are required for interactions with the BRCA2, POLH, and RAD51C proteins (PMID: 24141787, 24485656). While functional studies have not been performed to directly test the effect of this variant on PALB2 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine