NM_024675.4(PALB2):c.3103A>G (p.Ile1035Val) AND Familial cancer of breast

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Oct 30, 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:: RCV000196785.14

Allele description [Variation Report for NM_024675.4(PALB2):c.3103A>G (p.Ile1035Val)]

NM_024675.4(PALB2):c.3103A>G (p.Ile1035Val)

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.3103A>G (p.Ile1035Val)

HGVS:

NC_000016.10:g.23621372T>C
NG_007406.1:g.24986A>G
NM_024675.4:c.3103A>GMANE SELECT
NP_078951.2:p.Ile1035Val
NP_078951.2:p.Ile1035Val
LRG_308t1:c.3103A>G
LRG_308:g.24986A>G
LRG_308p1:p.Ile1035Val
NC_000016.9:g.23632693T>C
NM_024675.3:c.3103A>G

Protein change:

I1035V

Links:

dbSNP: rs863224783

NCBI 1000 Genomes Browser:

rs863224783

Molecular consequence:

NM_024675.4:c.3103A>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000255096	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 15, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27443514, 34284872, 35762214, 28492532
SCV000785829	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Dec 19, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27443514, 26315354 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV004019107	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Mar 30, 2023)	unknown	clinical testing	Citation Link,
SCV004201991	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 30, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutational profile of hereditary breast and ovarian cancer - Establishing genetic testing guidelines in a developing country.

Krivokuca A, Mihajlovic M, Susnjar S, Spasojevic IB, Minic I, Popovic L, Brankovic-Magic M.

Curr Probl Cancer. 2022 Feb;46(1):100767. doi: 10.1016/j.currproblcancer.2021.100767. Epub 2021 Jul 10.

PubMed [citation]

PMID:: 34284872

Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma.

Xia B, Biswas K, Foo TK, Gomes TT, Riedel-Topper M, Southon E, Kang Z, Huo Y, Reid S, Stauffer S, Zhou W, Zhu B, Koka H, Yepes S, Brodie SA, Jones K, Vogt A, Zhu B, Carter B, Freedman ND, Hicks B, Yeager M, et al.

Hum Mutat. 2022 Oct;43(10):1396-1407. doi: 10.1002/humu.24427. Epub 2022 Jul 12.

PubMed [citation]

PMID:: 35762214
PMCID:: PMC9444938

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000255096.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1035 of the PALB2 protein (p.Ile1035Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with endometrial cancer, chordoma, and hereditary breast and ovarian cancer (PMID: 27443514, 34284872, 35762214). ClinVar contains an entry for this variant (Variation ID: 216750). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function. Experimental studies have shown that this missense change affects PALB2 function (PMID: 35762214). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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 Counsyl, SCV000785829.2

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

#	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 Myriad Genetics, Inc., SCV004019107.1

#	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 classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

#	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 Baylor Genetics, SCV004201991.1

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

#	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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