chr16-23636231-C-G

Position:

chr16-23636231-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024675.4(PALB2):c.315G>C(p.Glu105Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,684 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E105Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 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:12B:1

Conservation

PhyloP100: -0.566

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08226743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.315G>C	p.Glu105Asp	missense_variant	4/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.315G>C	p.Glu105Asp	missense_variant	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251116

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.0000356

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152010

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 28, 2023	This missense variant replaces glutamic acid with aspartic acid at codon 105 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 individuals affected with breast and/or ovarian cancer (PMID: 22241545, 30651582) and in an individual affected with childhood-onset leukemia (PMID: 31721781). This variant also has been reported in several cancer case-control studies. In two breast cancer case-control studies, this variant has been detected in 7/7051 female breast cancer cases and 5/11241 unaffected controls (PMID: 30287823) and in 4/60466 cancer cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010032). This variant has been detected in 2/1005 pancreatic cancer cases and 6/23705 unaffected individuals (PMID: 32980694) and 2/7636 prostate cancer cases and 1/12366 unaffected individuals (PMID: 31214711). This variant has been identified in 7/282494 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	Ambry Genetics	Mar 21, 2023	The p.E105D variant (also known as c.315G>C), located in coding exon 4 of the PALB2 gene, results from a G to C substitution at nucleotide position 315. The glutamic acid at codon 105 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported in multiple unique cohorts of breast and/or ovarian cancer patients, but has also been reported in healthy control populations (Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80; Decker B et al. J Med Genet, 2017 11;54:732-741; Momozawa Y et al. Nat Commun. 2018 10;9:4083; Krivokuca A et al. J Hum Genet, 2019 Apr;64:281-290). This amino acid position is not 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	Feb 24, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 21, 2017	- -

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	PALB2: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Dec 30, 2022	PM2_SUP, 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, Yukihide Momozawa. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, one of whom also had ovarian cancer but harbored a BRCA1 pathogenic variant, pancreatic cancer, and in unaffected controls (Tischkowitz 2012, Decker 2017, Momozawa 2018, Krivokuca 2019, Mizukami 2020); This variant is associated with the following publications: (PMID: 32980694, 30651582, 28779002, 30404791, 30287823, 22241545) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	Variant summary: PALB2 c.315G>C (p.Glu105Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251116 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.315G>C has been reported in the literature in individuals affected with Breast Cancer (e.g., Tischkowitz_2012, Krivokuca_2019), pancreatic cancer (e.g., Mizukami_2020), and ovarian cancer (e.g., Prokofyeva_2023, Krivokuca_2019). Additionally one Japanese case-control association study on 7,051 unselected breast cancer cases and 11,241 female controls showed no association of this variant with breast cancer along with a final assessment as benign (Momozawa_2018); conversely, another Japanese case-control study on 1,005 pancreatic cancer patients and 23,705 controls reported the variant with an odds ratio of 7.9 (95% CI: 0.8-44.1; Mizukami_2020). These reports do not provide unequivocal conclusions about association of the variant with PALB2-associated cancers. At-least one co-occurrence with another pathogenic variant has been reported (BRCA1 c.1054G>T, p.Glu352*) in a 46 year old with HBOC and a family history of breast cancer, providing supporting evidence for a benign role (Krivocuca_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30651582, 30287823, 22241545, 37013556, 28779002, 32980694). ClinVar contains an entry for this variant (Variation ID: 126718). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Apr 14, 2022

- -

PALB2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2024

The PALB2 c.315G>C variant is predicted to result in the amino acid substitution p.Glu105Asp. This variant was reported in individuals with breast, ovarian, pancreatic, or biliary tract cancers; however, this variant was also documented in control individuals (supplementary data 1, Momozawa et al. 2018. PubMed ID: 30287823; Table S6, Mizukami et al. 2020. PubMed ID: 32980694; Table S2, Okawa et al. 2023. PubMed ID: 36243179; Prokofyeva et al. 2023. PubMed ID: 37013556). This variant was also documented in an individual from a hereditary breast and ovarian cancer (HBOC) cohort; however, this individual also carried a nonsense BRCA1 variant (subject #ID347 in Table A.1 and Table A.2, Krivokuca et al. 2022. PubMed ID: 34284872). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126718/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 105 of the PALB2 protein (p.Glu105Asp). This variant is present in population databases (rs515726108, gnomAD 0.005%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22241545, 30287823, 30651582, 34284872). ClinVar contains an entry for this variant (Variation ID: 126718). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.51

M_CAP

Benign

0.022

MetaRNN

Benign

0.082

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

REVEL

Benign

0.025

Sift

Uncertain

0.022

Sift4G

Uncertain

0.034

Polyphen

0.019

Vest4

0.11

MutPred

0.14

Gain of sheet (P = 0.0827);

MVP

0.34

MPC

0.057

ClinPred

0.044

GERP RS

0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.047

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