NM_024675.4(PALB2):c.3251C>T (p.Ser1084Leu) AND Familial cancer of breast

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 27, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000114610.20

Allele description [Variation Report for NM_024675.4(PALB2):c.3251C>T (p.Ser1084Leu)]

NM_024675.4(PALB2):c.3251C>T (p.Ser1084Leu)

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.3251C>T (p.Ser1084Leu)

Other names:

p.S1084L:TCG>TTG

HGVS:

NC_000016.10:g.23607963G>A
NG_007406.1:g.38395C>T
NM_024675.4:c.3251C>TMANE SELECT
NP_078951.2:p.Ser1084Leu
NP_078951.2:p.Ser1084Leu
LRG_308t1:c.3251C>T
LRG_308:g.38395C>T
LRG_308p1:p.Ser1084Leu
NC_000016.9:g.23619284G>A
NM_024675.3:c.3251C>T
p.S1084L

Protein change:

S1084L

Links:

dbSNP: rs62625271

NCBI 1000 Genomes Browser:

rs62625271

Molecular consequence:

NM_024675.4:c.3251C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial
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
SCV000255100	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 27, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23824750, 26315354, 31586400, 32048105, 28492532
SCV000489200	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Sep 1, 2016)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17200668, 26315354, 23824750 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV004019649	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Benign (Mar 31, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000255100

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 27, 2024)

germline

clinical testing

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

SCV000489200

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Sep 1, 2016)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV004019649

Myriad Genetics, Inc.

criteria provided, single submitter

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

Benign
(Mar 31, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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

A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor.

Rodrigue A, Margaillan G, Torres Gomes T, Coulombe Y, Montalban G, da Costa E Silva Carvalho S, Milano L, Ducy M, De-Gregoriis G, Dellaire G, Araújo da Silva W Jr, Monteiro AN, Carvalho MA, Simard J, Masson JY.

Nucleic Acids Res. 2019 Nov 18;47(20):10662-10677. doi: 10.1093/nar/gkz780.

PubMed [citation]

PMID:: 31586400
PMCID:: PMC6847799

Missense PALB2 germline variant disrupts nuclear localization of PALB2 in a patient with breast cancer.

Toh MR, Low CE, Chong ST, Chan SH, Ishak NDB, Courtney E, Kolinjivadi AM, Rodrigue A, Masson JY, Ngeow J.

Fam Cancer. 2020 Apr;19(2):123-131. doi: 10.1007/s10689-020-00163-8.

PubMed [citation]

PMID:: 32048105

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000255100.13

#	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 replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1084 of the PALB2 protein (p.Ser1084Leu). This variant is present in population databases (rs62625271, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 23824750, 26315354, 32048105). ClinVar contains an entry for this variant (Variation ID: 126727). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31586400, 32048105). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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, SCV000489200.2

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

#	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., SCV004019649.1

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

Description

This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.

#	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: May 1, 2024

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