rs773831304

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_024675.4(PALB2):c.2792T>G(p.Leu931Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000808 in 1,608,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L931P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:1

Conservation

PhyloP100: 5.59

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.2792T>G	p.Leu931Arg	missense_variant	8/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.2792T>G	p.Leu931Arg	missense_variant	8/13	1	NM_024675.4	P1
	ENST00000561764.1 linkuse as main transcript	n.571A>C		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250918

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135740

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000824

AC:

AN:

1456170

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724762

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000254

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	-	- -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 931 of the PALB2 protein (p.Leu931Arg). This variant is present in population databases (rs773831304, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24556926, 25452441, 30086788, 30651582, 33980423). ClinVar contains an entry for this variant (Variation ID: 186840). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395, 31757951). 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, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 12, 2022	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 01, 2023	The p.L931R variant (also known as c.2792T>G), located in coding exon 8 of the PALB2 gene, results from a T to G substitution at nucleotide position 2792. The leucine at codon 931 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Catucci I et al. Genet. Med. 2014 Sep;16(9):688-94; Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11; Krivokuca A et al. J. Hum. Genet., 2019 Apr;64:281-290; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Penkert J et al. Breast Cancer Res., 2018 08;20:87; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant was also reported in 2/107 Macedonian individuals with a clinical history of hereditary polyposis or hereditary non-polyposis colorectal cancer who underwent multi-gene panel testing (Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). In one homology-directed DNA repair (HDR) assay, this alteration was found to be functionally normal (Boonen RACM et al. Nat Commun, 2019 11;10:5296). However, this alteration was found to be functionally inconclusive in another homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 21, 2023	This missense variant replaces leucine with arginine at codon 931 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the variant protein is fully functional as determined by normal protein expression, homology-directed recombination activity and cell cycle control (PMID: 31636395, 31757951). This variant has been detected in at least 5 individuals affected with breast cancer (PMID: 24556926, 25452441, 30086788, 33471991, 33980423) and individual affected with ovarian cancer (PMID: 30651582) and suspected hereditary breast and ovarian cancer families (PMID: 31159747). This variant has been identified in 4/250918 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:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	PALB2: BP1, BS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 06, 2023	The frequency of this variant in the general population, 0.000035 (4/113416 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 33980423 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 31159747 (2019), 30086788 (2018), 29522266 (2018), 25452441 (2015), 24556926 (2014)), colorectal cancer (PMID: 31942411 (2019)), and healthy individuals (PMIDs: 32658311 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/PALB2)). Functional studies report the variant does not impact PALB2 function (PMIDs: 31636395 (2020), 31757951 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2017	This variant is denoted PALB2 c.2792T>G at the cDNA level, p.Leu931Arg (L931R) at the protein level, and results in the change of a Leucine to an Arginine (CTC>CGC). This variant has been observed in at least three individuals with breast cancer (Catucci 2014, Couch 2015). PALB2 Leu931Arg was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Leu931Arg occurs at a position that is conserved in mammals and is located within the region of interaction with RAD51, BRCA2, and POLH, and the region required for POLH DNA synthesis stimulation (Oliver 2009, Buisson 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Leu931Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 26, 2022

Variant summary: PALB2 c.2792T>G (p.Leu931Arg) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251898 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2792T>G has been reported in the literature in individuals affected with Breast Cancer (Couch_2015, Penkert_2018, Catucci_2014, Solmaz_2021), ovarian cancer (Krivokuca_2019), and colorectal cancer (Staninova-Stojovska_2019), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on homology directed repair and shows no significant impact on PALB2 function (Boonen_2019, Wiltshire_2020). Seven 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. -

Breast-ovarian cancer, familial, susceptibility to, 5

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Nov 02, 2023

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PALB2 p.Leu931Arg variant was identified in 3 of 4798 proband chromosomes (frequency: 0.0006) from individuals or families with breast cancer and was not identified in 1568 control chromosomes from healthy individuals (Catucci 2014, Couch 2015, ). The variant was also identified in dbSNP (ID: rs773831304) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, Color Genomics and one clinical laboratory), and in LOVD 3.0 (2x) databases. The variant was not identified in Cosmic, MutDB, and Zhejiang University databases. The variant was identified in control databases in 3 of 245710 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 3 of 111378 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu931 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.13

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Benign

-0.75

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.0

D;D

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.92

MutPred

0.71

.;Gain of methylation at L931 (P = 0.0115);

MVP

0.79

MPC

0.40

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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