16-23638084-G-C

Position:

chr16-23638084-G-C

Variant summary

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

The NM_024675.4(PALB2):c.94C>G(p.Leu32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:5O:1

Conservation

PhyloP100: -0.415

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:

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=0.21403447).

BP6

Variant 16-23638084-G-C is Benign according to our data. Variant chr16-23638084-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126781.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, not_provided=1, Uncertain_significance=9}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.94C>G	p.Leu32Val	missense_variant	2/13	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.94C>G	p.Leu32Val	missense_variant	2/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251478

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000821

AC:

120

AN:

1461708

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727158

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:

0.000103

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies demonstrate PARPi sensitivity and BRCA1 interaction comparable to wildtype (PMID: 31586400); Observed in individuals with personal or family history of breast, ovarian, and other cancers, as well as in unaffected controls (PMID: 23448497, 25503501, 26283626, 25186627, 25980754, 27153395, 28779002, 33471991, 34687117); This variant is associated with the following publications: (PMID: 24728327, 27425854, 23448497, 25980754, 26283626, 25503501, 25186627, 28779002, 27153395, 28259476, 20871615, 19369211, 33471991, 31586400, 34687117) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 20, 2022	BP4 -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 18, 2020	- -

Familial cancer of breast

Uncertain:1Benign:3

Likely benign, 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	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is considered 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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 06, 2016	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 14, 2022	The p.L32V variant (also known as c.94C>G), located in coding exon 2 of the PALB2 gene, results from a C to G substitution at nucleotide position 94. The leucine at codon 32 is replaced by valine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals diagnosed with breast cancer (Teo ZL et al. Breast Cancer Res. 2013 Feb 28;15:R17; Lerner-Ellis J et al. J Cancer Res Clin Oncol 2021 Mar;147(3):871-879). In one study, this alteration was reported in 6/13087 breast cancer cases and 1/5488 control individuals from the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). It was also reportedly detected in conjunction with a TP53 pathogenic mutation in an individual with early-onset breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 10, 2020	- -

not specified

Uncertain:1Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 24, 2021	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.94C>G, in exon 2 that results in an amino acid change, p.Leu32Val. This sequence change has been described in gnomAD with a frequency of 0.004% in the African-American sub-population (dbSNP rs151316635). The p.Leu32Val 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.Leu32Val substitution. This sequence change has been reported in multiple individuals affected with breast cancer (PMID: 23448497, 25503501, 26283626). In one study, an individual with early onset breast cancer was also found to be a carrier of a pathogenic TP53 sequence change (PMID: 25503501). Additionally, the PALB2 Leu32Val variant has been identified in two individuals undergoing multigene panel testing due to a history of a Lynch syndrome-related cancer and/or polyps (PMID: 25980754). Functional studies evaluating impact on protein function demonstrated that this variant has similar activity to wild-type (PMID: 31586400). Based on the currently available evidences, the clinical significance of the p.Leu32Val change remains unknown at this time. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 08, 2020	Variant summary: PALB2 c.94C>G (p.Leu32Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251478 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance (gnomAD). c.94C>G has been reported in the literature in individuals affected with breast cancer and Lynch syndrome but also, in controls (e.g. Maxwell_2015, Teo_2013, Thompson_2015, Tung_2015, Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a TP53 pathogenic variant (c.733G>A, p.G245S) has been reported in a patient with breast cancer (Maxwell_2015). Another study reported the variant in one heterozygous individual at high risk for breast and/or ovarian cancer with a classification of Likely benign, using lack of segregation in affected family members as evidence (Maxwell_2016). Experimental evidence evaluating an impact on protein function demonstrated the variant has similar activity to wild-type (Rodrigue_2019). Altogether, these data provide supporting evidence for a benign role. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; uncertain significance, n=7). Based on the evidence outlined above, the variant was classified as likely benign. -

PALB2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

The PALB2 c.94C>G variant is predicted to result in the amino acid substitution p.Leu32Val. This variant was identified in an individual suspected of having Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). It has also been identified in several individuals affected with breast cancer (Teo et al. 2013. PubMed ID: 23448497; Table S1, Maxwell et al. 2015. PubMed ID: 25503501; Table S4, Maxwell et al. 2016. PubMed ID: 27153395; Thompson et al. 2015. PubMed ID: 26283626; supplementary data, Tung et al. 2015. PubMed ID: 25186627). However, no further information was provided regarding its pathogenicity or segregation with disease in families. This variant was also identified in a healthy individual with no history of cancer (Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/126781/). 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. -

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.Leu32Val variant was identified in 6 of 12886 proband chromosomes (frequency: 0.00047) from individuals or families with breast cancer or Lynch syndrome and was present in 10 of 5358 control chromosomes (frequency: 0.002) from healthy individuals (Maxwell 2015, Teo 2013, Thompson 2015, Tung 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs151316635) as "With Likely benign,other allele ", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, GeneDx, PALB2 database and one clinical laboratory; as likely benign by one clinical laboratory) , MutDB , LOVD 3.0 (3x), and in Zhejiang University Database (1x). The variant was not identified in Cosmic, database. The variant was identified in control databases in 5 of 277244 chromosomes at a frequency of 0.000018 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24034 chromosomes (freq: 0.00004), European in 4 of 126730 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu32 residue is conserved in mammals but not in more distantly related organisms however four out of five 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

Eigen

Benign

-0.045

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

0.99

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.15

Sift

Uncertain

0.0070

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.44

MVP

0.71

MPC

0.35

ClinPred

0.74

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.13

gMVP

0.18

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

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