NM_024675.4(PALB2):c.3298_3307del (p.Thr1100fs) AND Familial cancer of breast

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 9, 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:: RCV003452322.3

Allele description [Variation Report for NM_024675.4(PALB2):c.3298_3307del (p.Thr1100fs)]

NM_024675.4(PALB2):c.3298_3307del (p.Thr1100fs)

Gene:

PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.3298_3307del (p.Thr1100fs)

HGVS:

NC_000016.10:g.23607909_23607918del
NG_007406.1:g.38442_38451del
NM_001407296.1:c.3238_3247del
NM_001407297.1:c.3226_3235del
NM_001407298.1:c.3136_3145del
NM_001407299.1:c.3114-4247_3114-4238del
NM_001407300.1:c.3019_3028del
NM_001407301.1:c.3202-4247_3202-4238del
NM_001407302.1:c.3040-4247_3040-4238del
NM_001407304.1:c.2413_2422del
NM_001407305.1:c.2413_2422del
NM_001407306.1:c.2413_2422del
NM_001407307.1:c.2251_2260del
NM_001407308.1:c.2229-4247_2229-4238del
NM_001407309.1:c.2229-4247_2229-4238del
NM_001407310.1:c.2317-4247_2317-4238del
NM_001407311.1:c.2317-4247_2317-4238del
NM_001407312.1:c.1510_1519del
NM_001407313.1:c.1414-4247_1414-4238del
NM_001407314.1:c.832_841del
NM_024675.4:c.3298_3307delMANE SELECT
NP_001394225.1:p.Thr1080fs
NP_001394226.1:p.Thr1076fs
NP_001394227.1:p.Thr1046fs
NP_001394229.1:p.Thr1007fs
NP_001394233.1:p.Thr805fs
NP_001394234.1:p.Thr805fs
NP_001394235.1:p.Thr805fs
NP_001394236.1:p.Thr751fs
NP_001394241.1:p.Thr504fs
NP_001394243.1:p.Thr278fs
NP_078951.2:p.Thr1100Trpfs
NP_078951.2:p.Thr1100fs
LRG_308t1:c.3296_3305del
LRG_308:g.38442_38451del
LRG_308p1:p.Thr1100Trpfs
NC_000016.9:g.23619228_23619237del
NC_000016.9:g.23619230_23619239del
NM_024675.3:c.3296_3305delCGACTCTCAG
NM_024675.3:c.3298_3307del10

Protein change:

T1007fs

Molecular consequence:

NM_001407296.1:c.3238_3247del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407297.1:c.3226_3235del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407298.1:c.3136_3145del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407300.1:c.3019_3028del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407304.1:c.2413_2422del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407305.1:c.2413_2422del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407306.1:c.2413_2422del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407307.1:c.2251_2260del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407312.1:c.1510_1519del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407314.1:c.832_841del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_024675.4:c.3298_3307del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407299.1:c.3114-4247_3114-4238del - intron variant - [Sequence Ontology: SO:0001627]
NM_001407301.1:c.3202-4247_3202-4238del - intron variant - [Sequence Ontology: SO:0001627]
NM_001407302.1:c.3040-4247_3040-4238del - intron variant - [Sequence Ontology: SO:0001627]
NM_001407308.1:c.2229-4247_2229-4238del - intron variant - [Sequence Ontology: SO:0001627]
NM_001407309.1:c.2229-4247_2229-4238del - intron variant - [Sequence Ontology: SO:0001627]
NM_001407310.1:c.2317-4247_2317-4238del - intron variant - [Sequence Ontology: SO:0001627]
NM_001407311.1:c.2317-4247_2317-4238del - intron variant - [Sequence Ontology: SO:0001627]
NM_001407313.1:c.1414-4247_1414-4238del - intron variant - [Sequence Ontology: SO:0001627]

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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cytochrome c oxidase subunit 2, putative [Plasmodium malariae]
cytochrome c oxidase subunit 2, putative [Plasmodium malariae]
gi|1624467168|ref|XP_028863678.1|

Protein
PREDICTED: Salvelinus alpinus frataxin, mitochondrial (LOC111974382), mRNA
PREDICTED: Salvelinus alpinus frataxin, mitochondrial (LOC111974382), mRNA
gi|1343016841|ref|XM_024002100.1|

Nucleotide
RHEB [Athene cunicularia]
RHEB [Athene cunicularia]
Gene ID:113477285

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004187453	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Sep 15, 2023)	unknown	clinical testing	Citation Link,
SCV004338226	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 9, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17200671, 19609323, 20927582, 21165770, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004187453

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(Sep 15, 2023)

unknown

clinical testing

Citation Link,

SCV004338226

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 9, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Structural basis for recruitment of BRCA2 by PALB2.

Oliver AW, Swift S, Lord CJ, Ashworth A, Pearl LH.

EMBO Rep. 2009 Sep;10(9):990-6. doi: 10.1038/embor.2009.126. Epub 2009 Jul 17. Erratum in: EMBO Rep. 2017 Jul;18(7):1264. doi: 10.15252/embr.201744508.

PubMed [citation]

PMID:: 19609323
PMCID:: PMC2750052

See all PubMed Citations (5)

Details of each submission

From Myriad Genetics, Inc., SCV004187453.1

#	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 frameshift 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004338226.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Thr1100Trpfs*3) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 87 amino acid(s) of the PALB2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200671, 19609323, 20927582, 21165770). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are 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

Last Updated: Sep 29, 2024

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