chr16-23607907-C-T

Position:

chr16-23607907-C-T

Variant summary

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

The NM_024675.4(PALB2):c.3307G>A(p.Val1103Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000774 in 1,614,128 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 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:5

Conservation

PhyloP100: -0.670

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06756854).

BP6

Variant 16-23607907-C-T is Benign according to our data. Variant chr16-23607907-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126732.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.3307G>A	p.Val1103Met	missense_variant	12/13	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.3307G>A	p.Val1103Met	missense_variant	12/13	1	NM_024675.4	ENSP00000261584	P1
	ENST00000561764.1 linkuse as main transcript	n.185+524C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000596

AC:

AN:

251472

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000814

AC:

119

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000737

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

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:

0.0000761

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:3Benign:1

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

not specified

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2023	Variant summary: PALB2 c.3307G>A (p.Val1103Met) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) 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 0.00013 in 302930 control chromosomes, predominantly at a frequency of 0.00027 within the East Asian subpopulation in the gnomAD database. Due to the underrepresentation of East Asian subpopulation in the gnomAD database, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. In addition, this variant was also found at a frequency of 0.0006 in 4.7K Japanese individuals in jMorp database (healthy Japanese volunteers; PMID: 29069501). c.3307G>A has been reported in the literature in sequencing studies reporting individuals affected with Hereditary Breast And Ovarian Cancer ( example, Casadei_2011, Gonzalez-Garay_2013, Thompson_2015, Kim_2017, Momozawa_2018), individuals undergoing multigene panel testing for Lynch syndrome (example, Thompson_2015), extra hepatic bile duct cancer (example, Terashima_2019), in male and female control cohorts of unaffected Japanese individuals (example, Momozawa_2018) and recently classified as benign in a study evaluating population-based screening for hereditary colorectal cancer variants in Japan (Fujita_2020). These reports do not provide unequivocal conclusions about association of the variant with PALB2 associated Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (example, Wiltshire_2019). These results showed no damaging effect of this variant on homology directed repair (HDR) activity of PALB2. The following publications have been ascertained in the context of this evaluation (PMID: 24082139, 25980754, 21285249, 26283626, 27783279, 30287823, 31666926, 31636395, 33309985). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=4; VUS, n=8). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2022	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3307G>A, in exon 12 that results in an amino acid change, p.Val1103Met. This sequence change has been previously described in individuals with breast and other cancers as well as in a control population (PMID: 21285249, 27783279, 3028782 , 26283626, 33309985). Experimental studies showed no damaging effect of this variant on homology directed repair (HDR) activity of PALB2 (PMID: 31636395). This sequence change has been described in the gnomAD database with a global population frequency of 0.005% (dbSNP rs201657283). The p.Val1103Met change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val1103Met substitution. Due to insufficient evidences the clinical significance of the p.Val1103Met change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 29, 2015	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 2019	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. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 21, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate homology-directed repair comparable to wild-type (Wiltshire 2020); Observed in individuals with breast and other cancers as well as unaffected controls (Casadei 2011, Gonzalez-Garay 2013, Thompson 2015, Yurgelun 2015, Kim 2017, Momozawa 2018, Fujita 2020, Song 2021); This variant is associated with the following publications: (PMID: 21285249, 24082139, 26283626, 25980754, 27783279, 30287823, 32566746, 32546565, 27535533, 33309985, 31636395, 19609323, 20871615, 24485656) -

PALB2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2024

The PALB2 c.3307G>A variant is predicted to result in the amino acid substitution p.Val1103Met. This variant has been reported in individuals with breast cancer or Lynch syndrome cancers (Table S4, Casadei et al. 2011. PubMed ID: 21285249; Table S5, Gonzalez-Garay et al. 2013. PubMed ID: 24082139; Table 3, Thompson et al. 2015. PubMed ID: 26283626; Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Table 3, Kim et al. 2017. PubMed ID: 27783279; Data S1, Momozawa et al. 2018. PubMed ID: 30287823) as well as unaffected individuals (Data S1, Momozawa et al. 2018. PubMed ID: 30287823). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126732/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.41

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

.;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.96

N;N

REVEL

Benign

0.063

Sift

Benign

0.20

T;T

Sift4G

Benign

0.085

T;T

Polyphen

0.73

.;P

Vest4

0.23

MVP

0.24

MPC

0.058

ClinPred

0.024

GERP RS

-1.4

Varity_R

0.097

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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