NM_024675.4:c.315G>C

Variant names:

• chr16-23636231-C-G
• rs515726108
• NM_024675.4:c.315G>C

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).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:1
• Conservation: PhyloP100: -0.566

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]

ACMG classification

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 rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.315G>C	p.Glu105Asp	missense_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.315G>C	p.Glu105Asp	missense_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152010 Hom.: 0 Cov.: 32

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: 6 AN: 251116 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135698

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: 52 AN: 1461674 Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27 AN XY: 727100

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: 1 AN: 152010 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74232

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.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

Feb 10, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 30, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_SUP, BP4 -

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, Yukihide Momozawa. -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PALB2: BP4 -

Sep 19, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP1 -

Jan 18, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PALB2 c.315G>C (p.Glu105Asp) variant has been reported in the published literature in individuals with breast cancer (PMID: 30651582 (2019), 30287823 (2018), 28779002 (2017), 22241545 (2012)) and/or ovarian cancer (PMID: 30651582 (2019)), as well as multiple reportedly healthy individuals (PMID: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). The frequency of this variant in the general population, 0.000039 (5/129074 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:4

Feb 24, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 28, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 21, 2017

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PALB2-related disorder Uncertain:1

Feb 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 acute lymphoblastic leukemia, breast cancer, ovarian cancer, and/or prostate cancer (PMID: 22241545, 30287823, 30651582, 31214711, 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	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.025
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.034	D
Polyphen		0.019	B
Vest4		0.11
MutPred		0.14		Gain of sheet (P = 0.0827);
MVP		0.34
MPC		0.057
ClinPred		0.044	T
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

Other links and lift over

dbSNP: rs515726108; hg19: chr16-23647552;