NM_024675.4(PALB2):c.2074C>T (p.Gln692Ter) AND Familial cancer of breast

Germline classification:: Likely pathogenic (4 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:: RCV001030275.10

Allele description [Variation Report for NM_024675.4(PALB2):c.2074C>T (p.Gln692Ter)]

NM_024675.4(PALB2):c.2074C>T (p.Gln692Ter)

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.2074C>T (p.Gln692Ter)

Other names:

NM_024675.3(PALB2):c.2074C>T; p.Gln692Ter

HGVS:

NC_000016.10:g.23630080G>A
NG_007406.1:g.16278C>T
NM_024675.4:c.2074C>TMANE SELECT
NP_078951.2:p.Gln692Ter
NP_078951.2:p.Gln692Ter
LRG_308t1:c.2074C>T
LRG_308:g.16278C>T
LRG_308p1:p.Gln692Ter
NC_000016.9:g.23641401G>A
NM_024675.3:c.2074C>T

Protein change:

Q692*

Links:

dbSNP: rs587776415

NCBI 1000 Genomes Browser:

rs587776415

Molecular consequence:

NM_024675.4:c.2074C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

Recent activity

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daa73e10.y1 Cho Li treated gastrula Xenopus laevis cDNA clone IMAGE:4061658 5', ...
daa73e10.y1 Cho Li treated gastrula Xenopus laevis cDNA clone IMAGE:4061658 5', mRNA sequence
gi|12474745|gnl|dbEST|7596414|gb|BG 8.1|

Nucleotide
JGI_XZT71064.rev NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7790431 3'...
JGI_XZT71064.rev NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7790431 3', mRNA sequence
gi|57059959|gnl|dbEST|26945351|gb|C 87.1|

Nucleotide
BX705143 XGC-tadpole Xenopus tropicalis cDNA clone TTpA006i05 3', mRNA sequence
BX705143 XGC-tadpole Xenopus tropicalis cDNA clone TTpA006i05 3', mRNA sequence
gi|38367350|gnl|dbEST|20421150|emb| 143.1|

Nucleotide
JGI_CAAM4326.rev NIH_XGC_tropTe3 Xenopus tropicalis cDNA clone IMAGE:7678227 3',...
JGI_CAAM4326.rev NIH_XGC_tropTe3 Xenopus tropicalis cDNA clone IMAGE:7678227 3', mRNA sequence
gi|58631070|gnl|dbEST|27598645|gb|C 26.1|

Nucleotide
dg18b06.y1 Xenopus laevis gastrula non normalized Xenopus laevis cDNA clone IMAG...
dg18b06.y1 Xenopus laevis gastrula non normalized Xenopus laevis cDNA clone IMAGE:3748955 5', mRNA sequence
gi|11787992|gnl|dbEST|7126945|gb|BF 9.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001193181	Leiden Open Variation Database	no assertion criteria provided	Pathogenic (May 13, 2019)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 24556926, 25099575
SCV001226735	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 20, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17200668, 17200671, 17200672, 24136930, 24556926, 25099575, 28492532
SCV003915555	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)	Likely pathogenic (Apr 5, 2023)	germline	curation	Citation Link,
SCV004189369	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Sep 12, 2023)	unknown	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.

Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D; Breast Cancer Susceptibility Collaboration (UK)., Easton DF, Stratton MR.

Nat Genet. 2007 Feb;39(2):165-7. Epub 2006 Dec 31.

PubMed [citation]

PMID:: 17200668
PMCID:: PMC2871593

Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.

Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, Neveling K, Kelly P, Seal S, Freund M, Wurm M, Batish SD, Lach FP, Yetgin S, Neitzel H, Ariffin H, Tischkowitz M, Mathew CG, Auerbach AD, Rahman N.

Nat Genet. 2007 Feb;39(2):162-4. Epub 2006 Dec 31.

PubMed [citation]

PMID:: 17200671

See all PubMed Citations (7)

Details of each submission

From Leiden Open Variation Database, SCV001193181.1

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

Description

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001226735.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Gln692*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs587776415, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 24556926, 25099575). ClinVar contains an entry for this variant (Variation ID: 143966). 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 ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen, SCV003915555.1

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

Description

The c.2074C>T (p.Gln692Ter) variant in PALB2 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM5_Supporting)

#	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 Myriad Genetics, Inc., SCV004189369.1

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

Description

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

#	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

Last Updated: Sep 29, 2024

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