NM_024675.4(PALB2):c.1671_1676delinsCG (p.Ile558fs) AND Familial cancer of breast

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 11, 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:: RCV003452340.3

Allele description [Variation Report for NM_024675.4(PALB2):c.1671_1676delinsCG (p.Ile558fs)]

NM_024675.4(PALB2):c.1671_1676delinsCG (p.Ile558fs)

Gene:

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

Variant type:

Indel

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.1671_1676delinsCG (p.Ile558fs)

HGVS:

NC_000016.10:g.23634870_23634875delinsCG
NG_007406.1:g.11483_11488delinsCG
NM_001407296.1:c.1611_1616delinsCG
NM_001407297.1:c.1671_1676delinsCG
NM_001407298.1:c.1671_1676delinsCG
NM_001407299.1:c.1671_1676delinsCG
NM_001407300.1:c.1671_1676delinsCG
NM_001407301.1:c.1671_1676delinsCG
NM_001407302.1:c.1671_1676delinsCG
NM_001407304.1:c.786_791delinsCG
NM_001407305.1:c.786_791delinsCG
NM_001407306.1:c.786_791delinsCG
NM_001407307.1:c.786_791delinsCG
NM_001407308.1:c.786_791delinsCG
NM_001407309.1:c.786_791delinsCG
NM_001407310.1:c.786_791delinsCG
NM_001407311.1:c.786_791delinsCG
NM_001407312.1:c.-104-4406_-104-4401delinsCG
NM_001407313.1:c.-104-4406_-104-4401delinsCG
NM_001407314.1:c.49-5600_49-5595delinsCG
NM_024675.4:c.1671_1676delinsCGMANE SELECT
NP_001394225.1:p.Ile538fs
NP_001394226.1:p.Ile558fs
NP_001394227.1:p.Ile558fs
NP_001394228.1:p.Ile558fs
NP_001394229.1:p.Ile558fs
NP_001394230.1:p.Ile558fs
NP_001394231.1:p.Ile558fs
NP_001394233.1:p.Ile263fs
NP_001394234.1:p.Ile263fs
NP_001394235.1:p.Ile263fs
NP_001394236.1:p.Ile263fs
NP_001394237.1:p.Ile263fs
NP_001394238.1:p.Ile263fs
NP_001394239.1:p.Ile263fs
NP_001394240.1:p.Ile263fs
NP_078951.2:p.Ile558Glufs
NP_078951.2:p.Ile558fs
LRG_308t1:c.1671_1676delTATTCAinsCG
LRG_308:g.11483_11488delinsCG
LRG_308p1:p.Ile558Glufs
NC_000016.9:g.23646191_23646196delinsCG
NM_024675.3:c.1671_1676delTATTCAinsCG

Protein change:

I263fs

Molecular consequence:

NM_001407296.1:c.1611_1616delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407297.1:c.1671_1676delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407298.1:c.1671_1676delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407299.1:c.1671_1676delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407300.1:c.1671_1676delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407301.1:c.1671_1676delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407302.1:c.1671_1676delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407304.1:c.786_791delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407305.1:c.786_791delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407306.1:c.786_791delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407307.1:c.786_791delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407308.1:c.786_791delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407309.1:c.786_791delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407310.1:c.786_791delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407311.1:c.786_791delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_024675.4:c.1671_1676delinsCG - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407312.1:c.-104-4406_-104-4401delinsCG - intron variant - [Sequence Ontology: SO:0001627]
NM_001407313.1:c.-104-4406_-104-4401delinsCG - intron variant - [Sequence Ontology: SO:0001627]
NM_001407314.1:c.49-5600_49-5595delinsCG - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004187485	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Sep 11, 2023)	unknown	clinical testing	Citation Link,
SCV004673464	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 11, 2014)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25099575, 17200668, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004187485

Myriad Genetics, Inc.

criteria provided, single submitter

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

Pathogenic
(Sep 11, 2023)

unknown

clinical testing

Citation Link,

SCV004673464

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 11, 2014)

germline

clinical testing

PubMed (3)
[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

Breast-cancer risk in families with mutations in PALB2.

Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F, Tomiak E, Neuhausen SL, Teo ZL, Khan S, Aittomäki K, Moilanen JS, Turnbull C, Seal S, Mannermaa A, Kallioniemi A, Lindeman GJ, Buys SS, et al.

N Engl J Med. 2014 Aug 7;371(6):497-506. doi: 10.1056/NEJMoa1400382.

PubMed [citation]

PMID:: 25099575
PMCID:: PMC4157599

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

See all PubMed Citations (3)

Details of each submission

From Myriad Genetics, Inc., SCV004187485.1

#	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, SCV004673464.1

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

Description

While this particular sequence change has not been reported in the literature, truncating sequence changes in PALB2 are known to be pathogenic (PMID: 25099575, 17200668). For these reasons, this sequence change has been classified as Pathogenic. This sequence change deletes 4 nucleotides from exon 4 of the PALB2 mRNA (c.1671_1676delinsCG), causing a frameshift at codon 558. This creates a premature translational stop signal (p.Ile558Glufs*2) and is expected to result in an absent or disrupted protein product.

#	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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