NM_024675.4:c.1540G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_024675.4(PALB2):c.1540G>A(p.Gly514Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G514G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:5

Conservation

PhyloP100: 0.686

Publications

7 publications found

Variant links:

COSMIC-nc: COSV55171426

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

PALB2 Gene-Disease associations (from GenCC):

hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
Fanconi anemia complementation group N
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 3
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
familial ovarian cancer
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

PALB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.046556532).

BP6

Variant 16-23635006-C-T is Benign according to our data. Variant chr16-23635006-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 232748.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4 link	c.1540G>A	p.Gly514Arg	missense_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 link	c.1540G>A	p.Gly514Arg	missense_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000107

AC:

AN:

251484

AF XY:

0.0000662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000327

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.000131

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Nov 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PALB2 c.1540G>A (p.Gly514Arg) variant has been reported in the published literature in individuals with breast cancer (PMID: 30287823 (2018), 33471991 (2021) see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)), colorectal cancer (PMID: 33309985 (2020)), biliary tract cancer (PMID: 36243179 (2022)) and pancreatic cancer (PMID: 32980694 (2020)). This variant has also been identified in unaffected individuals (PMID: 33309985 (2020), 32980694 (2020) 30287823 (2018), 36243179 (2022), 33471991 (2021) see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). The frequency of this variant in the general population, 0.00078 (27/34592 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Oct 27, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 14, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33309985, 32980694, 30287823, 33471991, 36243179) -

Aug 08, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PALB2 c.1540G>A (p.Gly514Arg) variant involves the alteration of a non-conserved nucleotide. The altered amino acid Gly514 is not clocated in any known domain. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. However, this variant was found in 8/121412 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.000691 (8/11578). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, one internal sample carries the variant of interest and a potential pathogenic APC variant (c.646-2A>G), further supporting the neutrality of the variant of interest. Taken together, this variant is classified as VUS-possibly benign. -

Familial cancer of breast

Uncertain:2Benign:2

Jan 14, 2025

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely 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]. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 17, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PALB2 c.1540G>A (p.Gly514Arg) missense change has a maximum subpopulation frequency of 0.078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer, prostate cancer, as well as in healthy controls (PMID: 30287823, 31206626, 31214711). It is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Jan 06, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 02, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 21, 2022

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3

Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PALB2 NM_024675.3 exon 4 p.Gly514Arg (c.1540G>A): This variant has not been reported in the literature and is present in 0.07% (27/34592) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-23646327-C-T). This variant amino acid Arginine (Arg) is present in several species including multiple mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Familial cancer of breast;C3150547:Pancreatic cancer, susceptibility to, 3

Uncertain:1

Mar 12, 2019

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.8

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

T;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;L

PhyloP100

0.69

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.4

N;D

REVEL

Benign

0.035

Sift

Benign

0.31

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.14

.;B

Vest4

0.19

MutPred

0.35

.;Gain of solvent accessibility (P = 0.0023);

MVP

0.39

MPC

0.15

ClinPred

0.056

GERP RS

2.6

Varity_R

0.058

gMVP

0.22

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over