chr16-23638084-G-C

Variant names:

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:13B: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=10}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4 link	c.94C>G	p.Leu32Val	missense_variant	Exon 2 of 13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 link	c.94C>G	p.Leu32Val	missense_variant	Exon 2 of 13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

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:13Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Dec 18, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

May 13, 2019

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. -

Jul 20, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Nov 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Sep 16, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 10, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_024675.4(PALB2):c.94C>G (p.Leu32Val) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Leu32Val variant is observed in 1/16,254 (0.0062%) alleles from individuals of gnomAD African background in gnomAD. The p.Leu32Val variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between leucine and valine, which is not likely to impact secondary protein structure as these residues share similar properties. For these reasons, this variant has been classified as Uncertain Significance. -

Familial cancer of breast

Uncertain:1Benign:3

Jan 06, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2015

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified

Uncertain:1Benign:1Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

May 24, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 23, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 7.7e-05 in 1606898 control chromosomes, predominantly at a frequency of 0.0001 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00016), allowing no conclusion about variant significance. However, the variant was also reported in 2/7325 European American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). The variant, c.94C>G, has been reported in the literature in individuals affected with breast cancer, and other tumor phenotypes, but was also found in several controls (e.g. (e.g. Maxwell_2015, Teo_2013, Thompson_2015, Tung_2015, Yurgelun_2015, Dorling_2021, Sylvester_2022, Tsyganov_2023). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with another pathogenic variant has been reported (TP53 c.733G>A, p.G245S; Maxwell_2015), providing supporting evidence for a benign role. Furthermore, another study reported the variant in a 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). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated the variant protein had similar activity to the wild-type (Rodrigue_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27153395, 25503501, 31586400, 23448497, 26283626, 25186627, 25980754, 33471991, 34687117, 37628606). ClinVar contains an entry for this variant (Variation ID: 126781). Based on the evidence outlined above, the variant was classified as likely benign. -

PALB2-related disorder

Uncertain:1

Jan 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5

Uncertain:1

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.

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

Other links and lift over