16-23636320-T-C

Variant summary

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

The NM_024675.4(PALB2):c.226A>G(p.Ile76Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000286 in 1,608,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. I76T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: -1.28

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038879067).

BP6

Variant 16-23636320-T-C is Benign according to our data. Variant chr16-23636320-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220168.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.226A>G	p.Ile76Val	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.226A>G	p.Ile76Val	missense_variant	4/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152082

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000329

AC:

AN:

243264

Hom.:

AF XY:

0.0000304

AC XY:

AN XY:

131736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000732

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1455998

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

724016

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

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:

0.0000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 30, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 22, 2016	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 19, 2021

Variant summary: PALB2 c.226A>G (p.Ile76Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. A recently published study evaluated this variant across three in-silico prediction algorithms, namely VEST3.0, M-CAP and REVEL and all three predicted a probably neutral/likely benign outcome (Rodriguez_2019). The variant allele was found at a frequency of 3.4e-05 in 263022 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.226A>G has been reported in the literature in at-least one individual affected with early onset breast cancer or familial breast cancer in a study that was limited to screening for coding exons in the PALB2 gene (example, Foulkes_2007). In another report, it was identified in an unaffected control (example, Ramus_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an experimental system that evaluated sensitivity to PARP inhibitor, Olaparib and the impact of PALB2 variants on BRCA1 and BRCA2 interaction by mammalian two-hybrid assay (Rodriguez_2019). The results of this functional study were internally consistent with the predictions from in-silico algorithms mentioned above. Five 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; VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Carcinoma of colon

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

Leiden Open Variation Database

Jan 31, 2017

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

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2022

Observed in an individual with breast cancer and in an unaffected control (Foulkes 2007, Ramus 2015); Published functional studies are conflicting: BRCA1 interaction and PARP inhibitor response was inconclusive while cell survival in response to olaparib was comparable to wild type (Rodrigue 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18053174, 26315354, 29522266, 33195396, 34298626, 20871615, 19369211, 31586400) -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 76 of the PALB2 protein (p.Ile76Val). This variant is present in population databases (rs541028076, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 18053174, 34326862). This variant is also known as c.5038A>G. ClinVar contains an entry for this variant (Variation ID: 220168). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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

0.078

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.66

Cadd

Benign

0.042

Dann

Benign

0.25

DEOGEN2

Benign

0.066

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0030

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.0087

MetaRNN

Benign

0.039

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.92

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

0.25

N;.

REVEL

Benign

0.042

Sift

Benign

0.96

T;.

Sift4G

Benign

1.0

T;.

Polyphen

0.0

B;.

Vest4

0.030

MVP

0.28

MPC

0.046

ClinPred

0.030

GERP RS

2.6

Varity_R

0.028

gMVP

0.011

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