16-23635002-T-C

Position:

chr16-23635002-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_024675.4(PALB2):c.1544A>G(p.Lys515Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,614,050 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 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.402

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12248054).

BP6

Variant 16-23635002-T-C is Benign according to our data. Variant chr16-23635002-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126607.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=6}. Variant chr16-23635002-T-C 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.1544A>G	p.Lys515Arg	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.1544A>G	p.Lys515Arg	missense_variant	4/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251486

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

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:

0.000123

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

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:

0.0000594

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PALB2: PS3:Supporting, BP1, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 13, 2024	The PALB2 c.1544A>G (p.Lys515Arg) variant has been reported in the published literature in several affected individuals with breast and/or ovarian cancer (PMIDs: 26283626 (2015), 27616075 (2016), 28873162 (2017), 29052111 (2018), 29522266 (2018), and 32658311 (2021)). It has also been found in reportedly healthy controls individuals (PMID: 21618343 (2011)). It was also reported in breast cancer cases as well as in reportedly healthy individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)).A functional study showed minimal reduction in HR activity and no effect on PARPi sensitivity compared to wild-type (PMID: 31757951 (2019)). The frequency of this variant in the general population, 0.0002 (7/35438 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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27328445, 29052111, 29338072, 26283626, 22241545, 21618343, 27616075, 25503501, 27930734, 21356067, 28873162, 27997549, 29522266, 31757951, 31159747) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 21, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 06, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 28, 2018	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. -

Familial cancer of breast

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Dec 04, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz. -
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	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 13, 2023

Variant summary: PALB2 c.1544A>G (p.Lys515Arg) results in a conservative amino acid change located in the DNA-binding domain (DBD, Nepomuceno_2020) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.3e-05 in 257362 control chromosomes, predominantly at a frequency of 0.0002 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), suggesting the variant may be a benign polymorphism found in the Latino subpopulation. c.1544A>G has been reported in the literature in individuals affected with cancer including Hereditary Breast and Ovarian Cancer and stomach adenocarcinoma but it was also reported in one healthy woman older than 50 years (Hauke_2018, He_2016, Hellebrand_2011, Kraus_2016, Lu_2015, Mandelker_2017, Maxwell_2014, Myszka_2017, Thompson_2015, Tischkowitz_2012, Tsaousis_2019, Akcay_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Moreover, the variant was reported in the FLOSSIES database in two women older than age 70 years who have never had cancer, providing supporting evidence for a benign role. One co-occurrence with a pathogenic variant has been reported internally (APC c.4873delC, p.Gln1625fs*25; internal LCA database). At least one functional study reports this variant has slightly reducing HR activity and no effect on PARPi sensitivity compared to WT (Boonen_2019). Twelve ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=9) and as likely benign (n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

PALB2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The PALB2 c.1544A>G variant is predicted to result in the amino acid substitution p.Lys515Arg. This variant has been previously reported in individuals with familial breast cancer (Thompson et al 2015. PubMed ID: 26283626; Kraus et al 2017. PubMed ID: 27616075). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD and in ClinVar it is classified as likely benign and a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/126607/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Nov 02, 2022

- -

Familial ovarian cancer

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PALB2 p.Lys515Arg variant was identified in 6 of 10468 proband chromosomes (frequency: 0.00057) from individuals or families with breast or ovarian cancer and was not identified in 4896 control chromosomes from healthy individuals (Hellebrand 2011, Kraus 2017, Maxwell 2015, Myszka 2017, Thompson 2015, Tischkowitz 2012). The variant was also identified in dbSNP (ID: rs515726072) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, Genedx, PALB2 database and three clinical laboratories), MutDB , and in LOVD 3.0 (1x), databases. The variant was not identified in Cosmic, or Zhejiang University Database. The variant was identified in control databases in 23 of 277248 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6468 chromosomes (freq: 0.00016), Latino in 7 of 34418 chromosomes (freq: 0.0002), European in 15 of 126730 chromosomes (freq: 0.00012), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys515 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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) 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. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Sep 11, 2024

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

.;L

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.0060

Sift

Benign

0.072

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.20

.;B

Vest4

0.11

MVP

0.43

MPC

0.074

ClinPred

0.047

GERP RS

3.3

Varity_R

0.054

gMVP

0.14

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