16-23630406-A-C

Position:

chr16-23630406-A-C

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP1

This summary comes from the ClinGen Evidence Repository: The c.1748T>G (p.Leu583Trp) variant in PALB2 is a missense variant predicted to cause a substitution of leucine by tryptophan at amino acid 583 (p.Leu583Trp). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000044 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA166979/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:12

Conservation

PhyloP100: 0.368

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.1748T>G	p.Leu583Trp	missense_variant	5/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.1748T>G	p.Leu583Trp	missense_variant	5/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250554

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135534

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2022	This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 583 of the PALB2 protein (p.Leu583Trp). This variant is present in population databases (rs587782151, gnomAD 0.005%). This missense change has been observed in individual(s) with ovarian or colorectal cancer (PMID: 31428572, 32546565). ClinVar contains an entry for this variant (Variation ID: 141972). 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 expected to disrupt PALB2 protein function. 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.1748T>G (p.Leu583Trp) variant in PALB2 is a missense variant predicted to cause a substitution of leucine by tryptophan at amino acid 583 (p.Leu583Trp). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000044 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP1) -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 14, 2022	The p.L583W variant (also known as c.1748T>G), located in coding exon 5 of the PALB2 gene, results from a T to G substitution at nucleotide position 1748. The leucine at codon 583 is replaced by tryptophan, an amino acid with similar properties. This alteration has been reported in several cancer cohorts including breast, ovarian, and colorectal cancer, as well as in control individuals in multiple studies (Decker B et al. J Med Genet, 2017 11;54:732-741; Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Song H et al. J Med Genet, 2021 05;58:305-313; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 07, 2022	This missense variant replaces leucine with tryptophan at codon 583 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and in unaffected individuals, including report in a breast cancer case-control meta-analysis in 2/60466 cases and 3/53461 unaffected individuals (PMID: 26315354, 28779002, 33471991; Leiden Open Variation Database DB-ID PALB2_010368); FLOSSIES database (https://whi.color.com/variant/16-23641727-A-C)). This variant has been identified in 5/250554 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26315354) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 09, 2022	The frequency of this variant in the general population, 0.000044 (5/113086 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28779002 (2017), 33471991 (2021)), ovarian cancer (PMID: 32546565 (2021)), and rectum cancer (PMID: 31428572 (2019)). The variant has also been identified in unaffected individuals (PMID: 33471991 (2021), 32546565 (2021), 26315354 (2015)). 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 and damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 15, 2023

Variant summary: PALB2 c.1748T>G (p.Leu583Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250554 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1748T>G has been reported in the literature as a VUS in settings of multigene panel testing for early onset colorectal cancer in at-least one individual with rectal cancer (example, Zhunussova_2019), breast cancer (Dorling_2021) and in unaffected controls (example, Dorling_2021, Ramus_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Prostate/PALB2-associated Cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26315354, 31428572). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.085

T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

.;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.4

N;D

REVEL

Benign

0.11

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.043

D;D

Polyphen

1.0

.;D

Vest4

0.41

MutPred

0.32

.;Gain of catalytic residue at L581 (P = 0.0025);

MVP

0.56

MPC

0.42

ClinPred

0.28

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over