chr16-23636248-G-A

Position:

chr16-23636248-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_024675.4(PALB2):c.298C>T(p.Leu100Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,613,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:7O:2

Conservation

PhyloP100: 0.0960

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:

PALB2 (HGNC:):

PALB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020982713).

BP6

Variant 16-23636248-G-A is Benign according to our data. Variant chr16-23636248-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126698.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=6, not_provided=2}. Variant chr16-23636248-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.298C>T	p.Leu100Phe	missense_variant	4/13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.298C>T	p.Leu100Phe	missense_variant	4/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

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:

0.000379

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251306

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000359

AC:

525

AN:

1461716

Hom.:

Cov.:

AF XY:

0.000351

AC XY:

255

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.0000562

Gnomad4 NFE exome

AF:

0.000437

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000197

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000379

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:7Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:5

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2022	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 10, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jun 18, 2018	- -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 10, 2022	- -

not provided

Uncertain:3Other:1

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. -
not provided, flagged submission	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	Not found to have a statistically significant association with breast cancer risk in a multi-ethnic exome array study (Haiman et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24448499, 25479140, 26283626, 21409391, 26315354, 25225577, 25186627, 26976419, 27060149, 26689913, 28767289, 28779002, 32659497, 32546565, 28259476, 35263119, 30541756, 28873162, 32885271, 33471991, 20871615, 19369211, 23555315, 34326862) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2023	The frequency of this variant in the general population, 0.00033 (42/129102 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 25225577 (2014), 26315354 (2015), 26976419 (2016), 28767289 (2017), and 28873162 (2017)). This variant has also been identified in healthy, unaffected individuals (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 26283626 (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. Based on the available information, we are unable to determine the clinical significance of this variant. -

Familial cancer of breast

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Pancreatic cancer, susceptibility to, 3

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PALB2 p.Leu100Phe variant was identified in 5 of 11930 proband chromosomes (frequency: 0.0004) from American, Canadian and Australian individuals or families with BRCA1/2 negative breast cancer, familial breast or breast/ovarian cancer, or ovarian cancer and was present in 4 of 10858 control chromosomes (frequency: 0.0003) from healthy individuals (Ramus_2015_26315354, Thompson_2015_26283626, Tung_2016_26976419, Wong_2011_21409391, Hartley_2014_25225577). The variant was identified in the following databases: dbSNP (ID: rs61756147) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified uncertain significance by GeneDx, Invitae, Ambry Genetics, Cancer Genetics Laboratory (Peter MacCallum Cancer Center) and the PALB2 database), Clinvitae (3x), LOVD 3.0 (1x), Zhejiang Colon Cancer Database (1x), and in control databases in 46 of 277092 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). Observation by population include â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34398 chromosomes (freq: 0.00003), European Non-Finnish in 42 of 126642 chromosomes (freq: 0.0003), and European Finnish in 2 of 25786 chromosomes (freq: 0.00008); it was not observed in the African, Ashkenazi Jewish, East Asian, and South Asian populations. The variant was not identified in Cosmic or MutDB. The p.Leu100 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of the variant Phe impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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. -

PALB2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2024

The PALB2 c.298C>T variant is predicted to result in the amino acid substitution p.Leu100Phe. This variant has been detected in patients with breast and ovarian cancer (Wong et al. 2011. PubMed ID: 21409391; Tung et al. 2016. PubMed ID: 26976419, Table A2; Hartley et al. 2014. PubMed ID: 25225577, Table S4; Ramus et al. 2015. PubMed ID: 26315354 Sup. Table 4; Kanchi et al. 2014. PubMed ID: 24448499, sup data 8) and pancreatic cancer (Shindo et al. 2017. PubMed ID: 28767289, referred to as c.298G>A; Grant et al. 2015. PubMed ID: 25479140, Sup. Table 1). However, it was detected in an equal number of cases and controls (2) in one of these studies (Ramus et al. 2015. PubMed ID: 26315354 Sup. Table 4). This variant is documented in the gnomAD general population database with a minor allele frequency of ~0.03% among non-Finnish Europeans and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/126698/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Fanconi anemia complementation group N

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 21, 2022

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 09, 2023

Variant summary: PALB2 c.298C>T (p.Leu100Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 293556 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In addition, this variant has been also reported in 3/7325 European American women who were older than age 70 years and cancer free (in the FLOSSIES database). c.298C>T has been reported in the literature in individuals affected with different types of cancer (Wong 2011, Haiman 2013, Hartley 2014, Tung 2014, Grant 2015, Ramus 2015, Lu 2015, Shindo 2017, Seligson_2019), but was also found in healthy controls (Thompson 2015, Ramus 2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant has been reported (BRCA1 c.5266dupC (p.Gln1756Profs*74), Tung 2014), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified as VUS (n=6), Likely Benign (n=5) and Benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome;C1835817:Fanconi anemia complementation group N

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as Uncertain significance and reported on 09-21-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.7

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.64

M_CAP

Benign

0.0080

MetaRNN

Benign

0.021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.79

REVEL

Benign

0.014

Sift

Benign

0.17

Sift4G

Benign

0.25

Polyphen

0.0080

Vest4

0.083

MVP

0.15

MPC

0.058

ClinPred

0.051

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.048

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