16-23607918-G-C

Position:

chr16-23607918-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6

The NM_024675.4(PALB2):c.3296C>G(p.Thr1099Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1099K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17B:2

Conservation

PhyloP100: 3.68

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 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_024675.4

BP6

Variant 16-23607918-G-C is Benign according to our data. Variant chr16-23607918-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142504.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=16}. Variant chr16-23607918-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.3296C>G	p.Thr1099Arg	missense_variant	12/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.3296C>G	p.Thr1099Arg	missense_variant	12/13	1	NM_024675.4	P1
	ENST00000561764.1 linkuse as main transcript	n.185+535G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251484

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000577

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:

0.0000868

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:6

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 12, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 24, 2023	The p.T1099R variant (also known as c.3296C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide position 3296. The threonine at codon 1099 is replaced by arginine, an amino acid with similar properties. This alteration has previously been reported in individuals at risk for hereditary breast, ovarian, and pancreatic cancers (Tung N et al. Cancer. 2015 Jan;121(1):25-33; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Aug;27;107(11); Decker B et al. J Med Genet. 2017 11;54:732-741; Abe T et al. J. Clin. Oncol. 2019 05;37(13):1070-1080; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This variant was also reported in 6/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med. 2020 Mar;22(3):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	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 24, 2023	This missense variant replaces threonine with arginine at codon 1099 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). A functional study has shown that this variant does not affect the homology-directed DNA repair function of PALB2 protein (PMID: 31636395). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 26976419, 28779002), bladder and colorectal cancer (PMID: 30883245), and ovarian cancer (PMID: 26315354), and this variant has been detected in a breast cancer case-control meta-analysis in 6/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010286). This variant has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/16-23619239-G-C), and it also has been identified in 17/282868 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

Familial cancer of breast

Uncertain:3Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2024	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	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]. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 29, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2023	Published functional studies demonstrate no damaging effect: homology directed DNA repair activity similar to wild type (PMID: 31636395); Observed in individuals with breast, ovarian, pancreatic, or colorectal cancer, but also in unaffected controls (PMID: 26315354, 28779002, 25186627, 31428572, 33471991, 30883245); 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: 25186627, 26315354, 26976419, 28779002, 31159747, 31422574, 30883245, 19609323, 20871615, 24485656, 33471991, 31428572, 31636395) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 12, 2023	In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 35402282 (2022), 26976419 (2016), 25186627 (2015)), ovarian cancer (PMID: 26315354 (2015)), and colorectal cancer (PMIDs: 31428572 (2019), 30883245 (2019)). The variant was also reported in an individual without a cancer diagnosis (PMID: 31422574 (2019)). The variant was detected in both cases and controls from a large breast cancer study (PMID: 33471991 (2021), https://databases.lovd.nl/shared/genes/PALB2). An in vivo functional study shows that the variant results in no damaging effect on protein function (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.00029 (3/10370 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 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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 11, 2023	Variant summary: PALB2 c.3296C>G (p.Thr1099Arg) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, 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 6.5e-05 in 263146 control chromosomes, predominantly at a frequency of 0.00016 within the South Asian subpopulation in the gnomAD database (5 occurrences). This frequency is equal to the estimated maximal expected allele frequency of a pathogenic PALB2 variant causing Hereditary Breast and Ovarian Cancer (0.00016), suggesting this may be a benign polymorphism. c.3296C>G has been reported in the literature as a VUS in individuals affected with Breast and/or Ovarian Cancer, colon and bladder cancer (example, Ramus_2015, Tung_2015, Tung_2016, Abe_2019, Zhunussova_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (ATM c.901+1G>A), providing supporting evidence for a benign role. At least one functional study reports the result of HDR assay showed no damaging effect of this variant (Wiltshire_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 35610400, 31422574, 26315354, 25186627, 26976419, 31636395, 31428572). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=16) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 14, 2017	- -

Fanconi anemia complementation group N

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with ovarian cancer [PMID 26315354] -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 10, 2020	- -

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

Mar 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Benign

-0.99

MutationAssessor

Benign

2.0

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

.;D

Vest4

0.87

MutPred

0.33

.;Gain of solvent accessibility (P = 0.008);

MVP

0.72

MPC

0.35

ClinPred

0.57

GERP RS

6.1

Varity_R

0.73

gMVP

0.58

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